Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial.

BACKGROUND: Dysregulated inflammation is associated with poor outcomes in COVID-19. We aimed to assess the efficacy of namilumab (a granulocyte-macrophage colony stimulating factor inhibitor) and infliximab (a tumour necrosis factor inhibitor) in hospitalised patients with COVID-19, to prioritise agents for phase 3 trials. METHODS: In this randomised, multicentre, multi-arm, multistage, parallel-group, open-label, adaptive, phase 2, proof-of-concept trial (CATALYST), we recruited patients (aged ≥16 years) admitted to hospital with COVID-19 pneumonia and C-reactive protein (CRP) concentrations of 40 mg/L or greater, at nine hospitals in the UK. Participants were randomly assigned with equal probability to usual care or usual care plus a single intravenous dose of namilumab (150 mg) or infliximab (5 mg/kg). Randomisation was stratified by care location within the hospital (ward vs intensive care unit [ICU]). Patients and investigators were not masked to treatment allocation. The primary endpoint was improvement in inflammation, measured by CRP concentration over time, analysed using Bayesian multilevel models. This trial is now complete and is registered with ISRCTN, 40580903. FINDINGS: Between June 15, 2020, and Feb 18, 2021, we screened 299 patients and 146 were enrolled and randomly assigned to usual care (n=54), namilumab (n=57), or infliximab (n=35). For the primary outcome, 45 patients in the usual care group were compared with 52 in the namilumab group, and 29 in the usual care group were compared with 28 in the infliximab group. The probabilities that the interventions were superior to usual care alone in reducing CRP concentration over time were 97% for namilumab and 15% for infliximab; the point estimates for treatment-time interactions were -0·09 (95% CI -0·19 to 0·00) for namilumab and 0·06 (-0·05 to 0·17) for infliximab. 134 adverse events occurred in 30 (55%) of 55 patients in the namilumab group compared with 145 in 29 (54%) of 54 in the usual care group. 102 adverse events occurred in 20 (69%) of 29 patients in the infliximab group compared with 112 in 17 (50%) of 34 in the usual care group. Death occurred in six (11%) patients in the namilumab group compared with ten (19%) in the usual care group, and in four (14%) in the infliximab group compared with five (15%) in the usual care group. INTERPRETATION: Namilumab, but not infliximab, showed proof-of-concept evidence for reduction in inflammation-as measured by CRP concentration-in hospitalised patients with COVID-19 pneumonia. Namilumab should be prioritised for further investigation in COVID-19. FUNDING: Medical Research Council.

The Impact of Indocyanine Green Angiography on Fat Necrosis in Deep Inferior Epigastric Perforator Flap Breast Reconstruction.

BACKGROUND: The deep inferior epigastric perforator flap (DIEP) is a widely known reliable option for autologous breast reconstruction. One common complication of DIEP procedures is fat necrosis. Consequences of fat necrosis include wound healing complications, pain, infection, and the psychological distress of possible cancerous recurrence. Clinical judgment alone is an imperfect method to detect at-risk segments of adipose tissue. Objective methods to assess perfusion may improve fat necrosis complication rates, reducing additional surgeries to exclude cancer and improve cosmesis for patients. METHODS: The authors performed a retrospective review of patients who underwent analysis of DIEP flap vascularity with or without intraoperative indocyanine green angiography (ICGA). Flap perfusion was assessed using intravenous ICGA and was quantified with both relative and absolute value units of fluorescence. Tissue with observed values less than 25% to 30% relative value units was resected. Postoperative outcomes and fat necrosis incidence were collected. RESULTS: Three hundred fifty-five DIEP flaps were included in the study, 187 (52.7%) of which were assessed intraoperatively with ICGA. Thirty-nine patients (10.9%) experienced operable fat necrosis. No statistically significant difference in incidence of postoperative fat necrosis was found between the 2 groups (P = 0.732). However, a statistically significant relationship was found between fat necrosis incidence and body mass index as both a continuum (P = 0.001) and when categorized as greater than 35 (P = 0.038). CONCLUSIONS: Although ICGA is useful for a variety of plastic surgery procedures, our retrospective review did not show a reduction in operable fat necrosis when using this technology.

Clinical presentation of women with pelvic source varicose veins in the perineum as a first step in the development of a disease-specific patient assessment tool.

OBJECTIVE: Pelvic venous incompetence can cause symptomatic varicose veins in the perineum, buttock, and thigh. Presentation, symptom severity, and response to treatment of pelvic source varicose veins are not well defined. Currently available tools to measure the severity of lower extremity venous disease and its effects on quality of life may be inadequate to assess disease severity in these patients. The purpose of this study was to evaluate the histories, demographics, and clinical presentations of women with pelvic source varicose veins and to compare these data to a population of women with nonpelvic source varicose veins. METHODS: A total of 72 female patients with symptomatic pelvic source varicose veins were prospectively followed up. Age, weight, height, parity, and birth weights of offspring were recorded. Both pelvic source varicose veins and saphenous incompetence were identified by duplex ultrasound. Patients were queried as to their primary symptoms, activities that made their symptoms worse, and time when their symptoms were most prominent. Severity of disease was objectively evaluated using the revised Venous Clinical Severity Score (rVCSS) and 10-point numeric pain rating scale (NPRS). RESULTS: Compared with women without a pelvic source of varicose veins (N = 1163), patients with pelvic source varicose veins were younger (mean, 44.6 ± 8.6 vs 52.6 ± 12.9 years; P < .001), had lower body mass index (mean, 21.9 ± 2.8 vs 25.8 ± 6.2; P < .001), and had larger babies than the U.S. population mean (mean, 3656 ± 450 g vs 3389 ± 466 g; P < .001). The most common symptoms were aching (68%), throbbing (47%), and heaviness (35%). In premenopausal patients, 70% noted that symptoms were worst during menses. NPRS score varied from 0 to 8 (mean, 4.9). The correlation between rVCSS (mean 5.6 ± 1.9) and NPRS was small (r = 0.26; P = .03). There was a modest correlation between older age and lower NPRS scores (r = -0.39; P < .001). CONCLUSIONS: Women with pelvic source varicose veins are a unique subset of patients. They are younger and thinner than those with nonpelvic source varicose veins, have larger infants than the general U.S. population, and have an inverse correlation between age and pain. As the majority of premenopausal patients have increased symptoms during menses, this may be due to hormonal influence. As it is poorly associated with patient-reported discomfort, the rVCSS is a poor tool for evaluating pelvic source varicose veins. A disease-specific tool for the evaluation of pelvic source varicose veins is critically needed, and this study is a first step in that endeavor.

Targeting specificity protein 1 transcription factor and survivin using tolfenamic acid for inhibiting Ewing sarcoma cell growth.

Transcription factor Specificity protein 1 (Sp1) and its downstream target survivin (inhibitor of apoptosis protein), play major roles in the pathogenesis of various cancers. Ewing Sarcoma (ES) is a common soft tissue/bone tumor in adolescent and young adults. Overexpression of survivin is also linked to the aggressiveness and poor prognosis of ES. Small molecule Tolfenamic acid (TA) inhibits Sp1 and survivin in cancer cells. In this investigation, we demonstrate a strategy to target Sp1 and survivin using TA and positive control Mithramycin A (Mit) to inhibit ES cell growth. Knock down of Sp1 using small interfering RNA (siRNA) resulted in significant (p < 0.05) inhibition of CHLA-9 and TC-32 cell growth as assessed by CellTiter-Glo assay kit. TA or Mit treatment caused dose/time-dependent inhibition of cell viability, and this inhibition was correlated with a decrease in Sp1 and survivin protein levels in ES cells. Quantitative PCR results showed that Mit treatment decreased the mRNA expression of both survivin and Sp1, whereas TA diminished only survivin but not Sp1. Proteasome inhibitor restored TA-induced inhibition of Sp1 protein expression suggesting that TA might cause proteasome-dependent degradation. Gel shift assay using ES cell nuclear extract and biotinylated Sp1 consensus oligonucleotides confirmed that both TA and Mit decreased DNA-binding activity of Sp1. These results demonstrate that both Mit and TA reduce expression of Sp1 and survivin, disrupt Sp1 DNA-binding and inhibit ES cell proliferation. This investigation suggests that targeting Sp1 and survivin could be an effective strategy for inhibiting ES cell growth.

Predictive value of interleukin-6 in post-cardiac arrest patients treated with targeted temperature management at 33 °C or 36 °C.

AIM: Post-cardiac arrest syndrome (PCAS) is characterized by systemic inflammation, however data on the prognostic value of inflammatory markers is sparse. We sought to investigate the importance of systemic inflammation, assessed by interleukin-6 (IL-6) in comatose survivors of out-of-hospital cardiac arrest. METHODS: A total of 682 patients enrolled in the Target Temperature Management (TTM) trial, surviving >24h with available IL-6 data were included. IL-6 was measured on days 1, 2 and 3 after return of spontaneous circulation. Severity of PCAS was assessed daily by the Sequential Organ Failure Assessment score. Survival status was recorded at 30 days. RESULTS: High levels of IL-6 at day 1-3 (all p<0.0001) were independently associated with severity of PCAS with no interaction of target temperature (all p=NS). IL-6 levels did not differ between temperature groups (p(interaction)=0.99). IL-6 levels at day 2 (p<0.0001) and day 3 (p<0.0001) were associated with crude mortality. Adjusted Cox proportional-hazards analysis showed that a two-fold increase of IL-6 levels at day 2 (HR=1.15 (95% CI: 1.07-1.23), p=0.0002) and day 3 (HR=1.18 (95% CI: 1.09-1.27), p<0.0001) were associated with mortality. IL-6 levels at day 3 had the highest discriminative value in predicting mortality (AUC=0.66). IL-6 did not significantly improve 30-day mortality prediction compared to traditional prognostic factors (p=0.08). CONCLUSIONS: In patients surviving >24h following cardiac arrest, IL-6 levels were significantly elevated and associated with severity of PCAS with no significant influence of target temperature. High IL-6 levels were associated with increased mortality. Measuring levels of IL-6 did not provide incremental prognostic value.

Invasive group A Streptococcus infections associated with liposuction surgery at outpatient facilities not subject to state or federal regulation.

IMPORTANCE: Liposuction is one of the most common cosmetic surgery procedures in the United States. Tumescent liposuction, in which crystalloid fluids, lidocaine, and epinephrine are infused subcutaneously before cannula-assisted aspiration of fat, can be performed without intravenous or general anesthesia, often at outpatient facilities. However, some of these facilities are not subject to state or federal regulation and may not adhere to appropriate infection control practices. OBJECTIVE: To describe an outbreak of severe group A Streptococcus (GAS) infections among persons undergoing tumescent liposuction at 2 outpatient cosmetic surgery facilities not subject to state or federal regulation. DESIGN: Outbreak investigation (including cohort analysis of at-risk patients), interviews using a standardized questionnaire, medical record review, facility assessment, and laboratory analysis of GAS isolates. SETTING AND PARTICIPANTS: Patients undergoing liposuction at 2 outpatient facilities, one in Maryland and the other in Pennsylvania, between July 1 and September 14, 2012. MAIN OUTCOMES AND MEASURES: Confirmed invasive GAS infections (isolation of GAS from a normally sterile site or wound of a patient with necrotizing fasciitis or streptococcal toxic shock syndrome), suspected GAS infections (inflamed surgical site and either purulent discharge or fever and chills in a patient with no alternative diagnosis), postsurgical symptoms and patient-reported experiences related to his or her procedure, and emm types, T-antigen types, and antimicrobial susceptibility of GAS isolates. RESULTS: We identified 4 confirmed cases and 9 suspected cases, including 1 death (overall attack rate, 20% [13 of 66]). One instance of likely secondary GAS transmission to a household member occurred. All confirmed case patients had necrotizing fasciitis and had undergone surgical debridement. Procedures linked to illness were performed by a single surgical team that traveled between the 2 locations; 2 team members (1 of whom reported recent cellulitis) were colonized with a GAS strain that was indistinguishable by laboratory analysis of the isolates from the case patients. Facility assessments and patient reports indicated substandard infection control, including errors in equipment sterilization and infection prevention training. CONCLUSIONS AND RELEVANCE: This outbreak of severe GAS infections was likely caused by transmission from colonized health care workers to patients during liposuction procedures. Additional oversight of outpatient cosmetic surgery facilities is needed to assure that they maintain appropriate infection control practices and other patient protections.

Validation of a novel murine wound model of Acinetobacter baumannii infection.

Patients recovering from traumatic injuries or surgery often require weeks to months of hospitalization, increasing the risk for wound and surgical site infections caused by ESKAPE pathogens, which include A. baumannii (the ESKAPE pathogens are Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). As new therapies are being developed to counter A. baumannii infections, animal models are also needed to evaluate potential treatments. Here, we present an excisional, murine wound model in which a diminutive inoculum of a clinically relevant, multidrug-resistant A. baumannii isolate can proliferate, form biofilms, and be effectively treated with antibiotics. The model requires a temporary, cyclophosphamide-induced neutropenia to establish an infection that can persist. A 6-mm-diameter, full-thickness wound was created in the skin overlying the thoracic spine, and after the wound bed was inoculated, it was covered with a dressing for 7 days. Uninoculated control wounds healed within 13 days, whereas infected, placebo-treated wounds remained unclosed beyond 21 days. Treated and untreated wounds were assessed with multiple quantitative and qualitative techniques that included gross pathology, weight loss and recovery, wound closure, bacterial burden, 16S rRNA community profiling, histopathology, peptide nucleic acid-fluorescence in situ hybridization, and scanning electron microscopy assessment of biofilms. The range of differences that we are able to identify with these measures in antibiotic- versus placebo-treated animals provides a clear window within which novel antimicrobial therapies can be assessed. The model can be used to evaluate antimicrobials for their ability to reduce specific pathogen loads in wounded tissues and clear biofilms. Ultimately, the mouse model approach allows for highly powered studies and serves as an initial multifaceted in vivo assessment prior to testing in larger animals.

Total autogenous mandibular reconstruction using virtual surgical planning.

Free fibula transfer has become the workhorse in mandibular reconstruction. Total mandibular reconstruction is an uncommon procedure with added complexity. Numerous techniques have been described for such reconstruction, many requiring a temporomandibular joint prosthesis. We present a novel method where simultaneous bilateral free fibula transfer utilizing preoperative virtual surgical planning was used to produce a total autogenous reconstruction. The virtual surgical planning allows to effectively quantify the bone stock required preoperatively and facilitates intraoperative modeling of the fibula. Therefore, a more anatomically correct reconstruction is obtained resulting in improved functional and aesthetic outcomes.

Composite fronto-orbital reconstruction using a subscapular chimeric flap.

Composite defects of the fronto-orbital region represent a reconstructive challenge. Total autogenous reconstruction requires a thin pliable skin flap along with a bony component that can be osteotomized predictably. The thoracodorsal artery perforator/scapular bone chimeric flap provides a reliable single-stage method to cover difficult composite forehead defects where local options are unsuitable or have been exhausted. We present a patient with a traumatic fronto-orbital defect that has been successfully reconstructed using this flap. The report of this case illustrates well the versatility of the subscapular system as a donor site for difficult composite posttraumatic defects where tissue components need to be inset in a complex three-dimensional fashion.

Complications of hydroxyapatite bone cement in secondary pediatric craniofacial reconstruction.

Hydroxyapatite cement has become a popular alternative to bone grafts in reconstructing the calvarium. Although animal studies have shown promising results with use of hydroxyapatite, human clinical studies have shown mixed results including significant rates of infection. This is a retrospective chart review during a 7-year period (1997-2003) of 20 patients who underwent secondary forehead cranioplasty with hydroxyapatite cement (Norian Craniofacial Reconstruction System). Basic demographics including age, sex, and diagnosis were identified. Characteristics of the defects were recorded including size, location, and depth (full versus partial thickness). The volume of hydroxyapatite and any adjunctive procedures were identified. The postoperative course was analyzed for length of follow-up and the presence of infections.Twenty patients were identified in which Norian had been used and 3 patients were lost to follow-up. Secondary forehead asymmetry was the most common presentation. The mean volume of hydroxyapatite used was 24.4 mL. All patients had initially acceptable aesthetic results. Of the 17 patients, 10 (59%) ultimately had infectious complications. Infection occurred on a mean of 17.3 months after surgery (range, 4 mo to 4 y), and the mean amount of hydroxyapatite used was 32.5 mL (infections) versus 14.3 mL (no infections). Of the 10 patients with complications, 9 required surgical debridement and subsequent delayed reconstruction. Although hydroxyapatite cement can yield excellent aesthetic results, its use in secondary reconstruction has yielded unacceptably high infection rates leading to discontinuation of its use in this patient population.

Simultaneous bilateral breast reconstruction with in-the-crease inferior gluteal artery perforator flaps.

The inferior gluteal artery perforator (IGAP) free flap represents an alternative technique for autogenous breast reconstruction in patients with insufficient abdominal donor tissue. Historically, patients underwent a staged approach for bilateral breast reconstruction with the IGAP because it is technically demanding and can be time consuming. The bilateral simultaneous IGAP can be performed effectively with 2 microsurgeons operating together. This is a retrospective study of 22 patients (44 flaps) who underwent bilateral breast reconstruction with bilateral IGAP flaps in one operation between January 2005 and December 2007. The following parameters were evaluated and compared to our published data with unilateral IGAP flap reconstruction: operating time, blood loss, flap weight, hospital length of stay, and perioperative complications. A follow-up patient survey was also conducted to gauge patient's satisfaction with the donor site and procedure. The flap survival rate was 100%. Complications included 1 patient with 1 flap with partial fat necrosis, 2 patients who required reoperation for venous congestion, 1 patient with a hematoma, 2 patients with delayed buttock wound healing, 2 patients requiring resuturing for buttock wound dehiscence, and 1 patient with resolved paresthesias. The majority of patients were satisfied with the procedure and donor site. In this study, we detail our experience with the inferior gluteal region as a reliable source of donor tissue and the simultaneous bilateral IGAP flap as an efficient method of breast reconstruction.

Decreasing listeriosis mortality in the United States, 1990-2005.

BACKGROUND: Listeria monocytogenes is among the most virulent foodborne pathogens, with 20% of clinical infections resulting in death. To explore listeriosis-associated mortality in the United States and to evaluate prevention efforts, we reviewed vital records over a 16-year period to assess demographic, temporal, and seasonal trends. METHODS: Nonperinatal listeriosis-associated deaths from 1990 through 2005 were identified from multiple-cause-coded death records and were combined with US census data to calculate mortality rates. Poisson regression was used to model time trends, and logistic regression was used to identify comorbid conditions associated with listeriosis on the death record. RESULTS: Of the 37,267,946 deaths occurring in the United States during the 16-year study period, 1178 included listeriosis on the death record. Listeriosis-related mortality rates decreased annually by 10.74% from 1990 through 1996 and by 4.26% from 1996 through 2005. Seasonal trends show a distinct peak in mortality from July through October. After adjustment for age, sex, and race/ethnicity, listeriosis was positively associated with human immunodeficiency virus (HIV) infection (odds ratio, 4.19; 95% confidence interval, 3.06-5.73), lymphoid and hematopoietic cancers (odds ratio, 5.27; 95% confidence interval, 4.47-6.22), and liver disease (odds ratio, 2.05; 95% confidence interval, 1.54-2.73) on the death record. CONCLUSIONS: Nonperinatal listeriosis-associated deaths in the United States have decreased, paralleling a decreasing trend in incidence. Strict monitoring of food manufacturing processes, as well as improved treatment for HIV infection, may have played influential roles in preventing human infections. Health care providers should be aware of seasonal listeriosis patterns, as well as conditions predisposing individuals to severe infection and death due to L. monocytogenes infection, to guide strategies for disease management and prevention.

A case of persistent anemia and alcohol abuse.

BACKGROUND: A 56-year-old male with a history of excess alcohol consumption for over 10 years and type 2 diabetes mellitus (diagnosed 14 years previously) presented to the accident and emergency department with severe anemia and a 1-day history of nausea and 'coffee ground' vomiting. He had been admitted to hospital on several occasions in the previous 18 months, primarily because of anemia, and had received 30 units of transfused blood during this period. Previous extensive investigations included six esophagogastroduodenoscopies and a colonoscopy, a barium follow-through study, and a radionucleotide Meckel's scan. The prior working diagnosis was anemia secondary to blood loss. INVESTIGATIONS: Laboratory investigations (full blood count [including reticulocytes], microscopic blood film examination, hematinics, liver function tests with direct and indirect bilirubin measurement, prothrombin time, and lactate dehydrogenase level), transjugular liver biopsy and bone-marrow biopsy. DIAGNOSIS: Alcohol-related anemia caused by acute hemolysis, sideroblastic anemia and cirrhosis. MANAGEMENT: Correction of anemia by blood transfusion (6 units), and prevention of recurrence by strict abstinence from alcohol.

Kidney cancer.

PURPOSE: We quantified the burden of kidney cancer in the United States by identifying trends in the use of health care resources and estimating the economic impact of the disease. MATERIALS AND METHODS: The analytical methods used to generate these results were described previously. RESULTS: The incidence of all stages of kidney cancer is increasing in America, particularly T1 disease. Rates are increasing more rapidly in the black than in the white population and survival is worse for black individuals at all stages of diagnosis. Total expenditures for kidney cancer were $401 million in 2000, representing a 46% increase from 1994. Approximately 85% of health care dollars spent on kidney cancer were for inpatient care with steady increases through the 1990s. Regarding treatment, more partial nephrectomies were performed in Medicare patients as the 1990s progressed. Health Care Cost and Utilization Project data showed an increase in the number of inpatient hospitalizations but this trend was not seen in the Centers for Medicare and Medicaid Services data set. Length of stay decreased from 1994 to 2000 in the Health Care Cost and Utilization Project database. The adoption of laparoscopic techniques began to appear in the Veterans Affairs data set in 2001 and it increased thereafter. CONCLUSIONS: Increasing trends in the incidence of and costs associated with kidney cancer have been apparent for more than 10 years. As the population ages and the prevalence of risk factors such as obesity and hypertension increases, the burden of disease will increase significantly. Consideration should be given to expanding tumor registries such as Surveillance, Epidemiology and End Results. Treatment databases could better characterize the cost and effectiveness of treatment for metastatic disease and of trends in the adoption of laparoscopy.

Testis cancer.

PURPOSE: We quantified the burden of testis cancer in the United States by identifying trends in its incidence, its treatment and the use of health care resources to estimate the economic impact of the disease. MATERIALS AND METHODS: The analytical methods used to generate these results were described previously. RESULTS: The overall incidence of testis cancer in the United States increased 46% between 1975 and 2001. During the same period the ratio of seminoma to nonseminoma increased and there were fewer men presenting with stage II and III tumors. Survival rates increased successively, attaining the current level of 95.9%. Treatment patterns changed and active surveillance increased as a primary treatment modality. Overall hospitalization rates for men with testis cancer decreased from 1.8/100,000 in 1994 and 1.4/100,000 in 2000. Care for white men shifted to the outpatient setting, which did not occur for black men. The estimated annual expenditure for testis cancer for privately insured individuals between ages 18 and 54 years was $6,236. National estimates of annual medical expenditures placed the total cost of treatment at $21.8 million in 2000, representing an increase of 10% over the total in 1994. Of men with testis cancer 16% missed work for treatment of the disease with an average of 8.4 total hours of work missed. CONCLUSIONS: The cost of testis cancer is estimated at almost $21.8 million annually. It appears to be increasing with time despite a shift to active surveillance treatments and less hospitalization.

Interstitial cystitis and painful bladder syndrome.

PURPOSE: We quantified the burden of interstitial cystitis/painful bladder syndrome on the health care system in the United States. MATERIALS AND METHODS: The analytical methods used to generate these results were described previously. Interstitial cystitis was defined based on International Classification of Diseases, 9th revision code 595.1 (interstitial cystitis). For painful bladder syndrome we used the definition International Classification of Diseases, 9th revision code 788.41 (urinary frequency) with code 625.8 (other specified symptoms associated with female genital organs) or 625.9 (unspecified symptoms associated with female genital organs). RESULTS: Between 1992 and 2001 there was a 2-fold increase in the rate of hospital outpatient visits and a 3-fold increase in the rate of physician office visits related to interstitial cystitis. The annualized rate was 102 office visits per 100,000 population. Ambulatory surgery for interstitial cystitis decreased. A diagnosis of interstitial cystitis was associated with a 2-fold increase in direct medical costs. Between 1994 and 2000 annual national expenditures for interstitial cystitis were stable at $37 million but annual costs for painful bladder syndrome increased from $481 million to $750 million. CONCLUSIONS: Although interstitial cystitis accounts for a small percent of health care visits, its economic burden is substantial. Because of misdiagnosis, the true burden of interstitial cystitis/painful bladder syndrome on the health care system in the United States is probably underestimated in administrative data that rely only on physician coding to identify the disorder. The greatest part of the disease burden is likely not captured in this economic analysis.

Male infertility.

PURPOSE: We assessed male infertility and its treatment in the United States by identifying trends in the use of health care resources and estimating the economic impact of such care. MATERIALS AND METHODS: The analytical methods used to generate these results were previously described. RESULTS: Inpatient hospitalizations for male infertility were relatively few with an overall rate of 0.9/100,000 population. Of these stays 55% were associated with inpatient management of varicocele and 749 of 797 occurred in a rural setting. Between 1994 and 1996 there were 55,411 ambulatory surgery visits with men 25 to 34 years old having the highest use rate of 61/100,000. Men living in the West had the lowest rate of ambulatory surgical visits, which was significantly lower than that for men living in the Northeast and Midwest (29/100,000 vs 104/100,000 and 72/100,000, respectively). The Veterans Affairs health system showed no geographic trend in infertility diagnosis and Hispanic men had the highest frequency of treatment for male infertility, followed by black and then white men. The National Survey for Ambulatory Surgery estimated that 67% of patients undergoing ambulatory surgery for male infertility had a diagnosis of varicocele. In 2000 total expenditures for treating primary male infertility were approximately $17 million. However, adding the cost for assisted reproduction technology cycles placed total cost at about $18 billion. CONCLUSIONS: Infertile males generally seek infertility care outside of traditional reimbursement patterns. For this reason obtaining accurate data regarding the costs associated with male fertility care has proved to be challenging. Given the expense of in vitro fertilization and its attendant technologies, emphasis should be placed on addressing the underlying causes of male infertility. Further systematic examination of the demographics and management of male reproductive dysfunction is warranted.

Bladder and upper tract urothelial cancer.

PURPOSE: While there are data available indicating the incidence and prevalence of bladder and upper tract urothelial cancer, population level data on resource use, costs and patterns of care for these cancers are limited. We quantified the economic impact of caring for patients with bladder and upper tract urothelial cancer, and determined the primary drivers for such costs in the population in the United States. MATERIALS AND METHODS: The analytical methods used to generate these results have been described previously. RESULTS: An increasing proportion of patients with bladder and upper tract urothelial cancer were being treated in the outpatient setting. Most care was provided by urologists and visit frequency was directly related to disease stage. Only a small proportion of patients potentially eligible for chemotherapy, ie those with advanced disease, sought specialized care from oncologists. Office based diagnostic tests such as cytology were not commonly done, although a substantial number of patients with bladder cancer underwent cystoscopy. The use of excretory urography in these patients was decreasing, while the use of computerized tomography was increasing. Ileal conduits were the most frequently performed type of urinary diversion following cystectomy. The cystectomy rate remained unchanged for a decade. Intravesical therapy was done infrequently in patients with bladder cancer. Annual costs for treating bladder and upper urinary tract cancers were $1 billion and $64 million, respectively, in 2000. These costs represented a $164 million increase over 1994 levels, which outpaced inflation. CONCLUSIONS: The costs of treating bladder cancer increased steadily during a 6-year period despite a decrease in inpatient care. Coupled with a lack of substantial change in transurethral resection and cystectomy rates, this suggests that the primary cost drivers are increased outpatient testing, eg computerized tomography and cystoscopy, and an increase in the number of diagnosed cases. Greater focus on selective use of testing modalities, preventive care such as smoking cessation and earlier identification of patients at risk may help curtail further expenditure with regard to managing bladder and upper urinary tract cancers.

Cryptorchidism and hypospadias.

PURPOSE: We quantified the burden of cryptorchidism and hypospadias in the United States by identifying trends in the use of health care resources and estimating the economic impact of the disease. MATERIALS AND METHODS: The analytical methods used to generate these results were described previously. RESULTS: Cryptorchidism is managed almost exclusively in the outpatient setting and insufficient data were available on inpatient health care use. Annual inpatient hospitalizations for hypospadias decreased by 75% between 1994 and 2000 from 2,669 (2.2/100,000 children) to 849 (0.6/100,000). Between 1992 and 2000 there were 611,647 physician office visits (96/100,000 per year) with undescended testis listed as the primary diagnosis. The rate of physician office visits for hypospadias by commercially insured boys younger than 3 years increased significantly from 429/100,000 in 1994 to 655/100,000 in 2002. The annualized rate of 18/100,000 in 1994 to 1996 remained relatively constant during these 3 years. Orchiopexy rates were highest in 0 to 2-year-old children, as generally recommended, but a substantial minority of these procedures was done in 3 to 10-year-old children. Geographic variation was noted with higher ambulatory surgery rates in the Northeast and Midwest than in the South and West. Data on commercially insured boys younger than 3 years revealed a 1.5-fold overall increase in the rate of hypospadias surgery from 321/100,000 in 1994 to 468/100,000 in 2002, reflecting the known increase in hypospadias incidence in the United States during the late 1990 s. CONCLUSIONS: Average cost per hospitalization for hypospadias exceeded $5,389 with costs per case higher in children 3 years or older, although there were more cases in children younger than 3 years. The cost per case of hypospadias was higher in the Northeast and South than in the other regions. Data on cryptorchidism are too sparse to provide insights into its downstream economic costs.