Beta-mannosidosis in a domestic cat associated with a missense variant in MANBA.

A 6-month-old cat of unknown ancestry presented for a neurologic evaluation due to progressive motor impairment. Complete physical and neurologic examinations suggested the disorder was likely to be hereditary, although the signs were not consistent with any previously described inherited disorders in cats. Due to the progression of disease signs including severely impaired motor function and cognitive decline, the cat was euthanized at approximately 10.5 months of age. Whole genome sequence analysis identified a homozygous missense variant c.2506G > A in MANBA that predicts a p.Gly836Arg alteration in the encoded lysosomal enzyme ß -mannosidase. This variant was not present in the whole genome or whole exome sequences of any of the 424 cats represented in the 99 Lives Cat Genome dataset. ß -Mannosidase enzyme activity was undetectable in brain tissue homogenates from the affected cat, whereas α-mannosidase enzyme activities were elevated compared to an unaffected cat. Postmortem examination of brain and retinal tissues revealed massive accumulations of vacuolar inclusions in most cells, similar to those reported in animals of other species with hereditary ß -mannosidosis. Based on these findings, the cat likely suffered from ß -mannosidosis due to the abolition of ß -mannosidase activity associated with the p.Gly836Arg amino acid substitution. p.Gly836 is located in the C-terminal region of the protein and was not previously known to be involved in modulating enzyme activity. In addition to the vacuolar inclusions, some cells in the brain of the affected cat contained inclusions that exhibited lipofuscin-like autofluorescence. Electron microscopic examinations suggested these inclusions formed via an autophagy-like process.

A Homozygous MAN2B1 Missense Mutation in a Doberman Pinscher Dog with Neurodegeneration, Cytoplasmic Vacuoles, Autofluorescent Storage Granules, and an α-Mannosidase Deficiency.

A 7-month-old Doberman Pinscher dog presented with progressive neurological signs and brain atrophy suggestive of a hereditary neurodegenerative disorder. The dog was euthanized due to the progression of disease signs. Microscopic examination of tissues collected at the time of euthanasia revealed massive accumulations of vacuolar inclusions in cells throughout the central nervous system, suggestive of a lysosomal storage disorder. A whole genome sequence generated with DNA from the affected dog contained a likely causal, homozygous missense variant in MAN2B1 that predicted an Asp104Gly amino acid substitution that was unique among whole genome sequences from over 4000 dogs. A lack of detectable α-mannosidase enzyme activity confirmed a diagnosis of a-mannosidosis. In addition to the vacuolar inclusions characteristic of α-mannosidosis, the dog exhibited accumulations of autofluorescent intracellular inclusions in some of the same tissues. The autofluorescence was similar to that which occurs in a group of lysosomal storage disorders called neuronal ceroid lipofuscinoses (NCLs). As in many of the NCLs, some of the storage bodies immunostained strongly for mitochondrial ATP synthase subunit c protein. This protein is not a substrate for α-mannosidase, so its accumulation and the development of storage body autofluorescence were likely due to a generalized impairment of lysosomal function secondary to the accumulation of α-mannosidase substrates. Thus, it appears that storage body autofluorescence and subunit c accumulation are not unique to the NCLs. Consistent with generalized lysosomal impairment, the affected dog exhibited accumulations of intracellular inclusions with varied and complex ultrastructural features characteristic of autophagolysosomes. Impaired autophagic flux may be a general feature of this class of disorders that contributes to disease pathology and could be a target for therapeutic intervention. In addition to storage body accumulation, glial activation indicative of neuroinflammation was observed in the brain and spinal cord of the proband.

Prostate Cancer Foundation-Department of Veterans Affairs Partnership: A Model of Public-Private Collaboration to Advance Treatment and Care of Invasive Cancers.

BACKGROUND: Prostate cancer is the most frequently diagnosed and treated cancer in the US Department of Veterans Affairs (VA). As the leading philanthropic source for prostate cancer research, the Prostate Cancer Foundation (PCF) entered into a unique public-private biomedical research partnership with the VA with the goal of addressing the urgent health challenges faced by veterans with prostate cancer. OBSERVATIONS: With a commitment of $50 million from PCF and the VA's vast medical center infrastructure, the PCF-VA partnership has established 12 precision oncology Centers of Excellence to date, forming a collaborative network called the Precision Oncology Program for Cancer of the Prostate (POPCaP) Network. A 4-year review reveals the importance of executive leadership, mission-driven advocacy, setting shared ambitious goals, maximizing existing infrastructure and human capital, recruiting talent and resources, and creating space for adaptation and iteration in the context of a learning health care system. CONCLUSIONS: The PCF-VA partnership seeks to continue translating clinical research into national standards of care for veterans and serves as an innovative model of public-private collaborations for future health initiatives.

Adverse Clinical Outcomes and Resource Utilization Associated with Methicillin-Resistant and Methicillin-Sensitive Staphylococcus aureus Infections after Elective Surgery.

BACKGROUND: Current studies of post-operative Staphylococcus aureus disease focus primarily on surgical site infections and are often limited to infections caused by methicillin-resistant Staphylococcus aureus (MRSA). The objective of this retrospective cohort analysis was to describe the occurrence of and outcomes associated with post-operative MRSA and methicillin-sensitive S. aureus (MSSA) infections in patients undergoing elective surgical procedures. METHODS: Data were extracted from Health Facts for inpatients aged 18 years or older with pre-defined International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure codes, meeting additional criteria indicating that the procedure was elective. Post-operative S. aureus infection was identified by one or more qualifying culture positive for MRSA or MSSA. Multivariable regression models compared patients with MRSA, MSSA, and no S. aureus infection. RESULTS: Among 34,866 qualifying patients, the incidence of S. aureus infections was 0.9% during the index admission and 1.7% within 90 d after elective surgery, of which 36.6% and 38.4% were MRSA, respectively. The highest rates were observed among patients undergoing general surgery (2.2% during index admission, 3.2% within 90 d) and plastic surgery (1.8% during index admission, 3.1% within 90 d). Patients with MRSA and MSSA experienced poorer outcomes than uninfected patients, based on index admission length of stay (LOS; mean, 30.2, 22.7, and 5.7 d, respectively), hospital charges ($165,651, $134,313, and $52,077), and hospital mortality (odds ratios, 6.4 for MRSA, 4.8 for MSSA versus uninfected patients). Relative to MSSA infection, MRSA infection was associated with greater total hospital LOS and hospital charges but not with increased re-admission or mortality. CONCLUSIONS: The burden of post-operative S. aureus infection is shared among elective surgical procedures, however, rates and types of infections vary. Whereas MRSA infection results in substantially greater health care cost and LOS, mortality and re-admission rates are similar among patients with MRSA and MSSA. In elective surgery, infection control and surveillance for both MRSA and MSSA are warranted.

Bringing care home: how telemonitoring can expand population health management beyond the hospital.

With emerging technology, patients are able to access the health care system from settings such as their homes, long-term care facilities, and schools. Telemonitoring allows care teams to oversee patients' clinical data captured and transmitted by specialized devices, with minimal involvement or manual effort, on a near real-time basis. This review was undertaken to provide insight into the capacity of telemonitoring technology to improve population health. Despite the potential of telemonitoring, evidence for its clinical, economic, and patient-reported benefits is inconclusive. Much of the outcome variation seen in the literature may be due to the heterogeneity of the interventions' characteristics, with some telemonitoring programs more effectively integrating into standard practice, targeting patients, and utilizing technology. A particular challenge is the ability to comprehensively leverage data to improve health outcomes. To accomplish this, the mass data collected by the devices must be aggregated with data from other clinical systems and used to develop predictive algorithms that can be embedded across the continuum of care. Innovations such as the Healthe Intent cloud-based platform can support a population health strategy by integrating telemonitoring and electronic health record data.

Outcomes associated with conventional versus lipid-based formulations of amphotericin B in propensity-matched groups.

BACKGROUND: Lipid-based formulations of amphotericin B (LF-AMB) are indicated for treatment of invasive fungal infections in patients intolerant to conventional amphotericin B (CAB) or with refractory infections. Physicians still may choose to administer CAB to such patients. We described the use of CAB and LF-AMB in this population and quantified differences in post-amphotericin B length of stay (LOS) among survivors and hospital mortality in matched patients. METHODS: Data were extracted from Health Facts (Cerner Corporation, Kansas City, MO, USA) for a retrospective cohort analysis. Inpatients aged ≥18 years with evidence of fungal infection and with orders for LF-AMB or CAB on ≥2 days from January 2001 to June 2010 were identified. Patients were required to have renal insufficiency or other relative contraindications to use of CAB, exposure to nephrotoxic agents, or evidence of a CAB-refractory infection. Multilevel (hierarchical) mixed-effects logistic regression was used to determine factors associated with initial exposure to LF-AMB versus CAB. Multivariate adjustment of outcomes was done using propensity score matching. RESULTS: 655 patients were identified: 322 patients initiated therapy with CAB and 333 initiated treatment with LF-AMB. Compared to those initiating CAB, patients initiating LF-AMB had greater acuity and underlying disease severity. In unadjusted analyses, hospital mortality was significantly higher in the LF-AMB group (32.2% versus 23.7%; P = 0.02). After propensity score matching and covariate adjustment, mortality equalized and observed differences in LOS after amphotericin B initiation decreased. CONCLUSION: Among patients at risk for amphotericin B toxicity, differences between CAB and LF-AMB seen in crude outcomes analyses relate to channeling of sicker patients to initiate treatment with LF-AMB. Failing to account for differences among patients that drive clinical decision-making will result in inaccurate conclusions about the real-world effectiveness of different amphotericin B formulations.

Development and validation of a bedside risk score for MRSA among patients hospitalized with complicated skin and skin structure infections.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of complicated skin and skin structure infections (cSSSI). Patients with MRSA require different empiric treatment than those with non-MRSA infections, yet no accurate tools exist to aid in stratifying the risk for a MRSA cSSSI. We sought to develop a simple bedside decision rule to tailor empiric coverage more accurately. METHODS: We conducted a large multicenter (N=62 hospitals) retrospective cohort study in a US-based database between April 2005 and March 2009. All adult initial admissions with ICD-9-CM codes specific to cSSSI were included. Patients admitted with MRSA vs. non-MRSA were compared with regard to baseline demographic, clinical and hospital characteristics. We developed and validated a model to predict the risk of MRSA, and compared its performance via sensitivity, specificity and other classification statistics to the healthcare-associated (HCA) infection risk factors. RESULTS: Of the 7,183 patients with cSSSI, 2,387 (33.2%) had MRSA. Factors discriminating MRSA from non-MRSA were age, African-American race, no evidence of diabetes mellitus, cancer or renal dysfunction, and prior history of cardiac dysrhythmia. The score ranging from 0 to 8 points exhibited a consistent dose-response relationship. A MRSA score of 5 or higher was superior to the HCA classification in all characteristics, while that of 4 or higher was superior on all metrics except specificity. CONCLUSIONS: MRSA is present in 1/3 of all hospitalized cSSSI. A simple bedside risk score can help discriminate the risk for MRSA vs. other pathogens with improved accuracy compared to the HCA definition.

Treatment of candidemia with echinocandins: data on hospital resource use from a real world setting.

OBJECTIVE: Real-world data on patients treated with echinocandins for candidemia are limited. This study examined the effect of three echinocandin-based treatment regimens on resource utilization in patients with Candida infection. RESEARCH DESIGN AND METHODS: A retrospective cohort study of patients hospitalized between 2005 and 2010 with a blood culture positive for Candida. Length of stay (LOS) following AF initiation (post-AF LOS) and total days with AF treatment were compared in patients treated with three different echinocandin regimens: patients with echinocandin only, patients who received fluconazole prior to an echinocandin (fluconazole-echinocandin), and patients who received an echinocandin prior to fluconazole (echinocandin-fluconazole). Generalized linear models were used to adjust for confounders. RESULTS: A total of 647 patients met inclusion criteria. Patients treated with echinocandin only were more acutely ill, having more organ dysfunction and sepsis. Unadjusted post-AF LOS was significantly greater in the groups that received both echinocandin and fluconazole (mean, 13.1 days for echinocandin-only vs 25.5 and 21.2 days for fluconazole-echinocandin and echinocandin-fluconazole groups, respectively, p<0.001). These groups also had a higher total number of days with AF orders. These differences remained after multivariate adjustment and in survivor-only analyses. Compared with echinocandin-only treatment, the average marginal effect of fluconazole-echinocandin and echinocandin-fluconazole regimens were associated with significantly longer adjusted post-AF LOS (by 7.2 days and 9.3 days, respectively, p<0.001) and significantly more adjusted total AF days (by 5.3 days for fluconazole-echinocandin and 6.5 days for echinocandin-fluconazole patients, p<0.001). Limitations included lack of visibility to specific reasons for therapy changes. CONCLUSIONS: Fluconazole before or after echinocandin was associated with significantly greater resource utilization than echinocandin use alone.