The aim of this study was to determine whether giving influenza vaccine to pregnant women can reduce the incidence of hospitalization due to influenza in their infants in the first year of life. This was a matched, hospital-based case-control study at Yale-New Haven Children’s Hospital. Case and control subjects were all aged <12 months at the time of their hospital admission from 2000 to 2009. All subjects were identified through hospital records. Cases consisted of infants admitted due to influenza infection. Infants who did not have influenza infection at the time of hospitalization matched to cases by date of birth and date of hospitalization (both within 4 weeks before or after) were used as controls. We contacted parents of all subjects to collect information on the subjects’ health and home setting and to get permission to review subjects’ and mothers’ hospital records and outpatient medical records. These were used to determine whether the subject or mother had received influenza vaccine or other vaccines and to identify underlying health conditions that could predispose to severe influenza infection. Conditional logistic regression was used to determine the relative risk of hospitalization for influenza infection for mothers who did or did not receive influenza vaccine during pregnancy or other times. The mothers of two (2.2 percent) of 91 cases and 31 (19.9 percent) of 156 controls aged <6 months and one (4.6 percent) of 22 cases and two (5.6 percent) of 36 controls aged >6 months received influenza vaccine during pregnancy. The effectiveness of influenza vaccine given to mothers in pregnancy in preventing hospitalization in their infants aged <6 months, adjusted for potential confounders, was 91.5 percent (95 percent CI: 61.7 percent-98.1 percent, p = 0.001). Influenza vaccine given to pregnant women was 91.5 percent effective in preventing hospitalization of their infants due to influenza in the first 6 months of life.
Retinoic acid (RA) is a small molecule capable of shunting developing T cells away from the Th17 lineage and toward the Treg phenotype, making it a potentially useful therapeutic for autoimmune and inflammatory diseases. However, therapy can be complicated by systemic toxicity and unpredictable bioavailability, making a targeted drug delivery vehicle for local therapy desirable. A promising approach is the use of nanoparticles, which have been demonstrated to increase potency and decrease toxicity of therapies in a variety of disease models, including Th17 mediated diseases. We therefore constructed a nanoparticulate drug delivery platform from poly(lactic-co-glycolic acid) (PLGA) capable of encapsulating and releasing RA. Here we report the fabrication, characterization, and in vitro> bioactivity of this platform. We demonstrate that RA containing PLGA nanoparticles suppress IL-17 and IFN-gamma production and ROR-gamma(t) expression in T cells polarized toward the Th17 phenotype in vitro with similar potency to that of free drug. Furthermore, we show that these particles enhance TGF-beta dependent Foxp3 expression and IL-10 production of T cells in vitro with similar potency to free RA. Finally, we demonstrate that T cells polarized toward the Th17 phenotype in the presence of free RA and nanoparticulate RA have similarly suppressed ability to induce IL-6 production by fibroblasts. Our findings demonstrate the feasibility of RA delivery via biodegradable nanoparticles and represent an exciting technology for the treatment of autoimmune and inflammatory diseases.
We hypothesized that activated platelets induce monocyte-to-dendritic cell (DC) differentiation. The aims of this study were to: 1) determine the role that platelets play, if any, in the signaling of monocyte to DC differentiation; 2) determine the mechanism of action by which platelets induce monocyte-to-DC differentiation; and 3) use this knowledge to advance cancer immunotherapy.
To achieve these ends: 1) Parallel-plate flow chambers were designed to deliver monocytes at a controlled level of platelet exposure, with phenotype and genotype assessed following overnight incubation; 2) blocking antibodies and proteins were used to assess for the significance of particular monocyte-platelet interactions in the mechanism; and 3) additional experiments and mathematical modeling were performed to extrapolate our new mechanistic knowledge to enhance extracorporeal photochemotherapy (ECP), an immunotherapy in clinical use.
Results showed direct correlation between platelet exposure and level of DC differentiation following overnight incubation (p < 0.0001). A detailed mechanism was determined involving p-selectin and other proteins expressed by activated platelets. This mechanistic knowledge permitted intelligent modification of ECP.
We conclude that platelets induce monocyte-to-DC differentiation. The rapidity and efficiency of this induction suggests the possibility that this is a physiologic mechanism employed in vivo for DC differentiation. Possible exploitation of this mechanism may prove beneficial in cancer immunotherapy.
The most widely used method of creating tissue engineered vascular grafts (TEVGs) for in vivo implantation consists of seeding autologous bone marrow cells (BMCs) onto biodegradable scaffolds. In this model of TEVG development, it has traditionally been thought that stem cells and endothelial progenitor cells (EPCs) within the seeded bone marrow population gave rise to the cells of the neovessel. Recent work in our lab indicates that the seeded BMCs are not incorporated into the neovessel and are actually rapidly lost from the implanted scaffold. Here we show the feasibility of noninvasively monitoring this process by tracking ultrasmall superparamagnetic iron oxide (USPIO)-labeled macrophages with MRI. Murine macrophages were labeled with USPIO through in vitro culture in media containing 2mg/ml of USPIO. The USPIO-labeled macrophages were seeded onto polyglycolic acid (PGA) scaffolds that were surgically implanted as inferior vena cava interposition grafts in SCID/bg mice. Images were then obtained using a 4.7T Bruker horizontal bore scanner with an optimized RARE spin echo sequence and a multislice-multiecho sequence to determine the T2 relaxation time with serial imaging. The T2 signal was found to be significantly lower immediately following implantation of the USPIO labeled scaffolds (T2 = 44±6.8 vs. 71±10.2) but increased rapidly to a value identical to that of control implants seeded with unlabeled macrophages (T2 = 63±12 vs. 63±14). This strongly indicates the rapid loss of seeded cells from the scaffolds, a finding verified using Prussian blue staining for iron containing macrophages on histological sections of explanted TEVGs. Our findings provide further support for the paradigm shift away from BMC neovessel incorporation toward the host cell-based population of implanted TEVGs. Furthermore, we demonstrate one of the first successful applications of noninvasive MR imaging for serial study of cellular level processes in tissue engineering.
The current recommendations for antiretroviral-naïve patients support initiating HIV-infected patients on a once-daily (QD) regimen. However, seropositive pregnant women are often initiated or changed to a twice-daily (BID) regimen due to the historical preference of zidovudine. Our 10-year retrospective cohort study aims to compare the efficacy and safety between QD (n = 20) and BID (n = 50) regimens in HIV-infected pregnant women. We hypothesize there will be no difference between the two dosing regimens. Using multivariate regression analysis to adjust for confounding variables, we found no statistical difference (adjusted odds ratio 0.26, 95 percent confidence interval 0.1,1.2; p = 0.099) in the quantity of patients who achieved a viral load < 50 copies/mL by the time of delivery between the QD group (80 percent) and the BID group (66 percent). Similarly, we found no difference in maternal or neonatal adverse effects, including preterm delivery, low birth weight, and pregnancy complications between our two cohorts. In summary, our study suggests QD dosing is non-inferior to BID dosing and may be a safe alternative for the HIV-infected pregnant population.
Healthcare-associated tuberculosis (TB) transmission occurs in resource-limited health facilities, putting patients and healthcare workers (HCWs) at risk. TB infection control (IC) can prevent such transmission but is inadequately implemented. We attempted to better characterize HCW TB IC implementation. We hypothesized that TB IC implementation would correlate in the manner predicted by the Information-Motivation-Behavioral skills (IMB) behavioral model. We conducted direct observations of TB IC behavior and staff questionnaires of TB IC IMB and behavior at two district hospitals (Church of Scotland Hospital, COSH, and Charles Johnson Memorial Hospital, CJM) in rural South Africa. Direct observations were conducted on 10 to 14 consecutive working days. Observed TB IC practices varied greatly by department (natural ventilation: 50.7-97.0 percent, respirator use: 5.0-100.0 percent). Questionnaires were completed by 123 HCWs at COSH and 75 at CJM. Information levels were generally high at both hospitals. Motivation responses were generally appropriate, though 29.4 percent would not be bothered “very much” by catching TB, and 22.8 percent thought TB IC was not worth the effort. Behavioral skills assessment indicated that HCWs found the majority of TB IC procedures to be easy to perform, though respondents highlighted several discrete tasks as being relatively difficult, especially those relating to personal HIV testing and relocation to low-risk departments if HIV-positive. When in high-risk TB areas of the hospital, more than half of respondents claimed to “always” wear a respirator (54.3 percent), instruct patients on cough hygiene (63.0 percent), and ensure effective natural ventilation (67.4 percent). Most (74.0 percent) knew their HIV status (81.0 percent at COSH, 63.8 percent at CJM, p = 0.012). Correlations were noted between self-reported TB IC implementation and several IMB variables, particularly those related to social support. A social support Motivational sub-scale correlated with self-reported respirator use (p = 0.002), cough hygiene instruction (p = 0.001), and natural ventilation (p = 0.006). A global model was created to compare IMB variables to aggregated self-reported TB IC behaviors. The only significant global scale variable was Motivation as a covariate of Behavioral skills (p < 0.000). IMB models were created for self-reported respirator use, cough hygiene instruction to patients, natural ventilation implementation, and knowledge of personal HIV status. The respirator IMB model performed much better than the others. Information did not vary significantly with other variables in any of the models. Results suggest that rather than focusing on improving staff information, efforts to increase TB IC implementation should focus on HCW Motivation and Behavioral skills development. TB IC implementation in this study compared favorably to other reports from the developing world. Social support, especially that of colleagues and supervisors, is an important element in ensuring better TB IC implementation, which is crucial to preventing healthcare-associated transmission. Though individual models require refinement, IMB modeling offers a promising avenue for further research and guiding interventions.
Purpose: Ovarian cancer has a poor prognosis, yet pathologic and clinical data do not accurately predict which patients will ultimately succumb to the disease. We previously reported an association between rs61764370, a germline functional variant in the 3’UTR of the KRAS oncogene, and epithelial ovarian cancer (EOC) risk. Here we evaluate this variant as a biomarker of clinical outcome and chemotherapy resistance in EOC.
Patients and Methods: Four groups of EOC patients with complete clinical data were genotyped for the KRAS-variant and analyzed: Sporadic EOC patients (n = 451); BRCA mutant EOC patients (n = 79); EOC patients treated with neoadjuvant chemotherapy (n = 122); and EOC patients treated adjuvantly with platinum-based chemotherapy after cytoreductive surgery (n = 292).
Results: The KRAS-variant predicts significantly worse survival for EOC patients over 55 years old by multivariate Cox regression analysis (HR = 1.71, 95 percent CI=1.09 - 2.69, p = 0.02). However, for the subgroup of EOC patients with known BRCA mutations, the KRAS-variant did not predict altered outcome (HR = 0.994, CI = 0.28-3.56, p = 0.99). KRAS-variant positive EOC patients respond poorly to neoadjuvant carboplatin and paclitaxel chemotherapy, having significantly more residual disease remaining after surgery (OR = 26.27, CI = 1.56- 441.83, p = 0.0232). In addition, EOC patients that harbor the KRAS-variant are more likely to be resistant to adjuvant platinum chemotherapy (OR = 2.86, CI = 1.13-7.23, p = 0.026).
Conclusions: These findings expand the potential importance of the KRAS-variant in EOC, from acting as a marker of risk to being a biomarker that predicts worse outcome, perhaps due to its association with platinum resistance. These data may ultimately help lead to treatment optimization and improved outcome for KRAS-variant positive EOC patients.
This study compares the rates of central venous stenosis in patients undergoing hemodialysis who underwent disruption of fibrin sheath with percutaneous transluminal angioplasty (PTA) balloons and those who underwent over-the-wire catheter exchange.
This study is a retrospective review of 209 PTA balloon disruption and 1,304 over-the-wire catheter exchange procedures. Approval from the Human Investigations Committee was obtained for this study. Up to 10-year follow-up was performed. A χ2 test was used to compare the rates of central venous stenosis after balloon disruption versus catheter exchange. A T-test was used to compare time to central venous stenosis development.
Of the 753 patients in the study, 127 patients underwent balloon disruption of fibrin sheath and 626 had catheter exchange. Within the balloon disruption group, 18/127 patients (14.2 percent) subsequently developed central venous stenosis, compared with 44/626 (7.0 percent) in the catheter exchange group (P < 0.01, χ2 test). Time to central venous stenosis development was approximately 3 years in both groups and not significantly different (1,371 and 1,010 days, P = 0.20). Twenty-five point two percent of patients in the balloon disruption group had four or more subsequent catheter exchanges versus 12.6 percent in the catheter exchange group (P < 0.01, χ2 test).
There is a possible association between PTA balloon disruption of fibrin sheath and late onset central venous stenosis. Since venography was not routinely performed in catheter exchange patients, future randomized studies are necessary to confirm these findings.
From antiquity, one of the primary goals of medicine has been the alleviation of patients’ suffering. Despite remarkable advances in modern science and technology, patients continue to experience suffering, which is frequently unnoticed and unaddressed by physicians.
Phenomenology incorporates an understanding of illness-as-lived, which provides the physician with a view more expansive than the purely biomedical model of disease. There exists a decisive gap between the way a physician thinks about disease and the way illness is experienced by the patient. As a result, there is a separation between the “lifeworlds” of the physician and patient. A fuller description of suffering in illness offers the physician an expanded paradigm of illness to enable her to narrow the gap between her own lifeworld and that of the patient. This thesis employs a clinically based phenomenological approach, observing the phenomena of disease and illness as they are encountered in the clinical setting, the nucleus of which is the doctor-patient relationship.
Suffering is certainly something that should be eliminated by all reasonable means and costs. It is also clear, however, that sometimes suffering is unavoidable in the patient’s experience of illness. We hold these two truths in tension. On the one hand, it is a duty for physicians to try to alleviate unnecessary suffering. But what about inescapable suffering, particularly in cases of chronic and terminal illness?
Viktor Frankl notes that meaning can be a powerful avenue to the elevation of the human person in moments of unavoidable suffering. This thesis proposes that suffering can be transfigured by way of meaning and that physicians can play a powerful role toward this end. The will to meaning is a means to gains such as love, self-transcendence, achievement of a good, and the dignity of the person amid the losses experienced in suffering. This work offers a novel contribution to the medical literature by demonstrating that unavoidable suffering potentially can be transformed into a positive experience and that the doctor-patient encounter can be instrumental in this pursuit.
Rather than waiting for systemic changes in healthcare or medical education, this thesis argues that physicians can be instrumental in the alleviation and transformation of suffering simply by adopting phenomenological personalism in the practice of medicine. Premised on a heightened attentiveness to the patient’s lifeworld, phenomenological personalism serves as a catalyst for the patient’s discovery of meaning in unavoidable suffering. This approach does not exclude the biomedical model, but rather expands the lifeworld of the physician so that she is able to acknowledge and address the uniqueness of the patient’s experience of suffering in illness. Thus, in moments of unavoidable suffering, a personal tragedy is transfigured into a human triumph.
In age-related macular degeneration (AMD), the outer blood-retinal barrier is exposed to various pathologic factors that can result in visual detriment. Two such stimuli include serum, as may be seen in neovascular AMD, and proinflammatory cytokines, which may be seen in neovascular and non-neovascular AMD. To examine effects of serum and cytokines in disease, we adapted an outer blood-retinal barrier culture model using human fetal retinal pigment epithelium (hfRPE) to investigate effects on tight junctions. Specifically, we focused on the claudin family and occludin tight junction proteins. HfRPE was cultured on filters in growth medium until quiescent monolayers were formed; cells were then either maintained in growth medium or switched to a serum-free medium. To study serum effects, serum-free medium maintained cells were exposed to serum in apical, basal, or both media chambers. To study cytokine effects, growth medium and serum-free medium cells were exposed to TNF-α (10ng/mL), IL-1β (10ng/mL), or INF-γ (5ng/mL) in both media chambers for 48 hours. Effects were measured at the functional level (transepithelial electrical resistance; ion selectivity), mRNA level (RT-PCR, quantitative, real-time RT-PCR), and protein level (immunoblotting, immunofluorescence). Claudin 19 was the predominant claudin with mRNA expression >20× that of any other claudin and exhibited protein expression in every cell. siRNA knockdown of claudin 19 resulted in functionally deficient tight junctions. Apical, corresponding to subretinal, serum increased TER 2-3× and altered ion selectivity; basal serum had no effect. Apical serum effects were accompanied by increases in occludin protein levels. TNF-α decreased TER and altered ion selectivity in both media conditions; IL-1β and INF-γ had little or inconsistent effects. TNF-α exposure lowered claudin 19 but raised claudin 2 and occludin levels. Preventing the increase of claudin 2 with an siRNA did not alter the effect of TNF-α; this suggests TNF-α decreased TER by a different mechanism. This culture model of the outer blood-retinal barrier in AMD suggests claudin 19 is essential for the formation of functional tight junctions. Subretinal serum results in a tightened outer blood-retinal barrier, which may be mediated by occludin; this tightening may help limit the spread of disease. Inflammatory cytokines, particularly TNF-α, appear to alter tight junction function and properties which may potentiate inflammatory diseases such as AMD.
Background: Admission rates vary by regions and states, but the extent by which variation in regional admission rates are related to variation in the medical need of populations and the association with hospital outcomes is unknown. To address these issues, we examine two cardiovascular conditions that differ in physician discretion to admit: acute myocardial infarction (AMI), less discretionary, and heart failure (HF), more discretionary. We first determined whether regional cardiovascular risk factors predict admission rates and then examined whether regional admission rates were related to 30-day risk-standardized mortality and readmission rates (RSMRs and RSRRs).
Methods: We used 2006-2008 Medicare ICD-9-CM claims data and the Medicare Denominator file to determine AMI and HF admission rates. The statewide prevalence of cardiovascular risk factors was obtained from the 2007 Behavioral Risk Factor Surveillance System. First, the relationship between statewide AMI and HF admission rates and cardiovascular risk factors was determined by a multivariate, least squares linear regression model. Second, hierarchical logistic models were used to estimate hospital RSMRs and RSRRs and then were aggregated to the level of hospital referral regions (HRRs). The correlation (R2) was obtained by linear regression to characterize the relationship between both AMI and HF admission rates and regional RSMRs and RSRRs. Where significant relationships were observed, “cross condition” analyses were performed, comparing admission rates of one condition against the RSMR or RSRR of the other in an effort to identify potentially confounded relationships.
Results: In the first analysis, cardiovascular risk factors explained 49 percent of the variation observed in statewide AMI admission rates and 50 percent of the variation in HF admission rates. In the second analysis, regional AMI admission rate was not correlated with AMI RSMR (R2 0.01, 95 percent CI 0.00-0.04). Regional HF admission rate was inversely correlated with HR RSMR (R2 0.13, 95 percent CI 0.07-0.21). Regional AMI hospitalization rate was weakly correlated with AMI RSRR (R2 0.05, 95 percent CI 0.02-0.11). Regional HF admission rate was modestly correlated with HF RSRR (R2 0.25, 95 percent CI 0.17-0.34). In the cross condition analyses, regional HF admission rate was not associated with AMI RSMR (R2 0.00, 95 percent CI 0.00-0.02) but was associated with AMI RSRR (R2 0.25, 95 percent CI 0.17-0.34).
Conclusion: Cardiovascular risk factors explain part, but not all, of the variation in AMI and HF admission rates. The modest association between regional HF admission rate, a more discretionary admission condition, and both AMI and HF RSRRs suggests a system propensity to patients. The same was not seen true of AMI, a less discretionary admission condition. The modest inverse relationship between regional HF admission rate and HF RSMR, which was not observed with AMI RSMR, suggests an unmeasured confounder affecting the HF RSMR model.
Biomarkers, such as estrogen receptor, are used to determine therapy and prognosis in breast carcinoma. Immunostaining assays of biomarker expression have a high rate of inaccuracy; for example, estimates are as high as 20 percent for estrogen receptor. Biomarkers have been shown to be heterogeneously expressed in breast tumors, and this heterogeneity may contribute to the inaccuracy of immunostaining assays. Currently, no evidence-based standards exist for the amount of tumor that must be sampled in order to correct for biomarker heterogeneity.
The purpose of this study is to determine the optimal number of 20X fields that are necessary to estimate a representative measurement of expression in a whole tissue section for selected biomarkers: estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), AKT, extracellular signal-regulated kinase (ERK), ribosomal protein S6 kinase 1 (S6K1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), cytokeratin, and microtubule-associated protein-Tau (MAP-Tau).
Two collections of whole tissue sections of breast carcinoma were immunostained for biomarkers. Expression was quantified using Automated Quantitative Analysis (AQUA). Simulated sampling of various numbers of fields (ranging from 1 to 35) was performed for each marker. The optimal number was selected for each marker via resampling techniques and minimization of prediction error over an independent test set.
The optimal number of 20X fields varied depending on the marker evaluated and ranged between three to14 fields. More heterogeneous markers, such as MAP-Tau, required a larger sample of 20X fields to produce representative measurement. The clinical implication of these findings is that small core needle breast biopsies may be inadequate to represent whole tumor biomarker expression for many markers. Also, for biomarkers newly introduced into clinical use, especially if therapeutic response is dictated by level of expression, the optimal size of tissue sample must be determined on a marker-by-marker basis.
Thyroid cancer increases in incidence and aggressiveness with age. The elderly are the fastest growing segment of the U.S. population. Reducing rates of rehospitalization would lower cost and improve quality of care. The SEER-Medicare linked database was used to identify patients >65 years with thyroid cancer who underwent thyroidectomy from 1997 to 2002. Patient and hospital characteristics were studied as predictors of rehospitalization. Outcomes were 30-day unplanned rehospitalization rate, cost, and length of stay (LOS) of readmission. Of 2,127 patients identified, 69 percent were female, 84 percent had differentiated thyroid cancer, and 52 percent underwent total thyroidectomy. Mean age was 74 years. One hundred seventy-one patients (8 percent) underwent 30-day unplanned rehospitalization. Rehospitalization was associated with increased comorbidity (17 percent for a Charlson index of moderate/high vs. 6 percent for an index of none; P < .001), advanced stage (22 percent for distant stage vs. 6 percent for local disease; P < .001), number of lymph nodes examined (12 percent for >10 nodes vs. 7 percent for 0 nodes; P = .011), increased LOS of index admission (mean of 4.8 days vs. 2.9 days; P < .001), and small hospital size (9 percent vs. 6 percent for large hospitals; P = .026). Patients with a complication during index hospital stay were more likely to be readmitted (14 percent vs. 6 percent; P < .001), while patients who saw an outpatient medical provider following index discharge returned less frequently (5 percent vs. 11 percent; P < .001). Forty-seven percent of readmissions were for endocrine-related causes. Mean LOS and cost of rehospitalization were 3.5 days and $5,921, respectively. Unplanned rehospitalization was associated with death at 1 year compared to non-rehospitalized patients (18 percent vs. 6 percent; P < .001). Rehospitalizations among Medicare beneficiaries with thyroid cancer following thyroidectomy are prevalent and costly. Further study of predictors could identify high-risk patients for whom enhanced preoperative triage, improved discharge planning, and increased outpatient support might prove cost-effective.
The treatment of neurosurgical disease in the developing world presents challenges on numerous levels, not the least of which are the litany of logistical and infrastructural barriers that stand in the way of delivering care. The scarcity of neurosurgeons combined with limited mobility in developing countries requires a reconsideration of approaches to treatment; this is particularly true of ventriculoperitoneal (VP) shunt insertion for the treatment of hydrocephalus. While VP shunt implantation is the mainstay of treatment in the United States, it is prone to failure requiring rapid access to neurosurgical care making shunt dependency a dangerous proposition in this setting. Endoscopic third ventriculostomy (ETV) offers an alternative to VP shunt dependency and has been shown to be effective in treating hydrocephalus at intervals of up to 14 months.
The purpose of this study is to compare the 5-year survival for children treated with endoscopic third ventriculostomy (ETV) to those treated with ventriculoperitoneal (VP) shunt implantation for myelomeningocele-associated hydrocephalus. Because of the well-known dangers of shunt dependency, it is hypothesized that patients treated with ETV will have a survival advantage when compared with patients treated with VPS at a follow-up interval of 5 years.
In order to address this hypothesis, a retrospective observational study of children treated with ETV or VP shunt implantation for myelomeningocele-related hydrocephalus at the CURE Children’s Hospital of Uganda was carried out, including a control group consisting of myelomeningocele patients who had not developed hydrocephalus.
Survival status was determined for 128 of 131 study participants (98 percent). Forty-seven of 128 (37 percent) of patients had expired at 5 years post-treatment, and 55 of 128 (42 percent) patients had expired at a mean follow-up interval of 84.4 months. Only two cases of death were attributable to the development of hydrocephalus, none as a result of treatment failure. Kaplan-Meier survival analysis found no statistically significant relationship between survival and method of treatment for hydrocephalus (p = 0.45), sex of patient (p = 0.53), HIV status (p = 0.69), age at repair (p = 0.34), or myelomeningocele level (p = 0.12). Survival analysis performed for districts with community based rehabilitation (CBR) programs and districts without CBR programs revealed a significant interaction (p = 0.001).
The uniformly high mortality across all groups suggests that the chief causes of long-term mortality are both powerful and independent of hydrocephalus. The only correlation with survival identified in this study, the presence of a CBR program providing in-home rehabilitation, fulfills both of these criteria: Myelomeningocele patients require long-term rehabilitation regardless of the development of hydrocephalus, and these programs exert a powerful influence on survival. This substantial difference in long-term survival highlights the fact that children in communities without CBR programs are not receiving life-saving supportive care, in part due to a lack of parental understanding of the need for longitudinal care. Established cultural beliefs about myelomeningocele, hydrocephalus, and disability in general also hampered efforts to improve survival. Understanding the practical barriers to the delivery of care in a developing country as well as the cultural mores through which diseases are understood are critical to effectively treating disease across cultures and continents.