Retrospective Evaluation of Rabbit Antithymocyte Globulin Induction in Heart Transplant Patients.

The dosing intensity of antithymocyte globulin as induction therapy in heart transplantation remains controversial. We sought to evaluate the efficacy and safety of rabbit antithymocyte globulin at a total dose of 4.5 mg/kg compared with <4.5 mg/kg. Methods: This was a retrospective study of consecutive patients who underwent heart transplantation from January 2016 to December 2018 at a single quaternary care center. Exposure was defined as full antithymocyte globulin (4.5 mg/kg total) induction compared with partial (<4.5 mg/kg) induction. The primary outcome was the incidence of The International Society for Heart and Lung Transplantation 1990 acute cellular rejection grade 2 or above at 2 y. Secondary outcomes were all-cause mortality, number of infections, and time to therapeutic tacrolimus levels. Cox proportional hazard models were used to compare rejection rates and mortality. Results: Of 201 patients, 61 received partial and 140 received full induction. There was no difference in the cumulative incidence of cellular rejection grade 2 or above (18% versus 11.4%, P = 0.209) within 2 y. The adjusted hazard ratio was 1.45 (confidence interval: 0.62-3.37, P = 0.388) for partial compared with full induction for any grade rejection. Landmark survival analysis conditional on survival to 1 mo showed no difference in mortality (P = 0.239). There was no difference in the incidence of infection within 3 mo of transplant (partial 29.5% versus full 20.0%, P = 0.140). Both groups achieved therapeutic tacrolimus levels by day 7 after initiation. Conclusions: There was no difference in overall risk for any grade cellular rejection between partial or full dose induction therapy. Additionally, there was no difference in medium-term mortality from landmark survival analysis.

Impact of valganciclovir prophylaxis duration on cytomegalovirus disease in high-risk donor seropositive/recipient seronegative heart transplant recipients.

BACKGROUND: Few data support use of 6 over 3 months of antiviral prophylaxis for cytomegalovirus (CMV) disease prevention in donor seropositive/recipient seronegative (D+R-) heart transplant recipients (HTR). METHODS: We retrospectively assessed CMV disease and outcomes in 310 adult HTR between July 5, 2005, and December 30, 2016, at our center. Valganciclovir (VGCV) prophylaxis was given for 3-6 months in the D+R- group. Multivariable models evaluated risk factors for CMV disease in patients who received 3 vs 6 months (±1 month) of prophylaxis, with investigation of inverse probability weighting to correct for confounding variables. RESULTS: The incidence of CMV disease among all patients and the D+R- group was 8.7% (27/310) and 26.5% (22/83), respectively, and included syndrome in 22.2% (6/27) and end-organ involvement in 77.8% (21/27). In a multivariable model, 6 vs 3 months of antiviral prophylaxis was not associated with reduced risk for CMV disease (OR 2.28 [95% CI 0.66, 7.91], P = .19). CMV disease in D+R- HTR was associated with higher rates of hospitalization (87.5% [14/16] vs 6.3% [1/16], P < .001) and for a longer duration than in matched D+R- controls without disease. CONCLUSIONS: Cytomegalovirus disease remains a major cause of morbidity in D+R- HTR. In contrast to documented benefit in D+R- lung and kidney recipients, VGCV duration of 6 months was not associated with a lower incidence of CMV disease in D+R- HTR compared to 3-month duration and should be reconsidered in this patient population.

Therapeutic Challenges for Elderly Patients with Primary Hyperparathyroidism.

Primary hyperparathyroidism (PHPT) predominantly affects older adults, and parathyroidectomy can achieve definitive cure in symptomatic PHPT and asymptomatic meeting surgical criteria. As the population continues to age, the treatment of PHPT in octogenarians and nonagenarians presents a clinical conundrum. This case series presents the management of eight patients 85 years of age and older diagnosed with PHPT. A retrospective chart review of patients diagnosed with primary hyperparathyroidism were identified in a single institution. Those patients 85 years of age and older who were followed up for over one year were included in this case series. The literature on treatment options for this age group was also reviewed. Eight cases of PHPT patients aged 88 ± 2.5 years old with a follow-up average of 5.6 ± 4.4 years were reported in our case series. Six PHPT patients were medically managed and two PHPT patients underwent parathyroid resection. Most of the medically managed PHPT patients except for one had long-term stability of disease for over five years. The treatment of PHPT diagnosed in patients over 85 years of age presents a clinical challenge for which there is no clear consensus guideline. Our case series supports that medical therapy is a feasible option for PHPT patients over 85 years old.

Mechanisms of Osteoblastic Bone Metastasis in Prostate Cancer: Role of Prostatic Acid Phosphatase.

Prostate cancer (PCa) preferentially metastasizes to bone, leading to complications including severe pain, fractures, spinal cord compression, bone marrow suppression, and a mortality of ∼70%. In spite of recent advances in chemo-, hormonal, and radiation therapies, bone-metastatic, castrate-resistant PCa is incurable. PCa is somewhat unique among the solid tumors in its tendency to produce osteoblastic lesions composed of hypermineralized bone with multiple layers of poorly organized type I collagen fibrils that have reduced mechanical strength. Many of the signaling pathways that control normal bone homeostasis are at play in pathologic PCa bone metastases, including the receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand/osteoprotegerin system. A number of PCa-derived soluble factors have been shown to induce the dysfunctional osteoblastic phenotype. However, therapies directed at these osteoblastic-stimulating proteins have yielded disappointing clinical results to date. One of the soluble factors expressed by PCa cells, particularly in bone metastases, is prostatic acid phosphatase (PAP). Human PAP is a prostate epithelium-specific secretory protein that was the first tumor marker ever described. Biologically, PAP exhibits both phosphatase activity and ecto-5'-nucleotidase activity, generating extracellular phosphate and adenosine as the final products. Accumulating evidence indicates that PAP plays a causal role in the osteoblastic phenotype and aberrant bone mineralization seen in bone-metastatic, castrate-resistant PCa. Targeting PAP may represent a therapeutic approach to improve morbidity and mortality from PCa osteoblastic bone metastases.

Compressed 3D and 2D digital images versus standard 3D slide film for the evaluation of glaucomatous optic nerve features.

SYNOPSIS: Clinicians can feel confident compressed three-dimensional digital (3DD) and two-dimensional digital (2DD) imaging evaluating important features of glaucomatous disc damage is comparable to the previous gold standard of stereoscopic slide film photography, supporting the use of digital imaging for teleglaucoma applications. BACKGROUND/AIMS: To compare the sensitivity and specificity of 3DD and 2DD photography with stereo slide film in detecting glaucomatous optic nerve head features. METHODS: This prospective, multireader validation study imaged and compressed glaucomatous, suspicious or normal optic nerves using a ratio of 16:1 into 3DD and 2DD (1024×1280 pixels) and compared both to stereo slide film. The primary outcome was vertical cup-to-disc ratio (VCDR) and secondary outcomes, including disc haemorrhage and notching, were also evaluated. Each format was graded randomly by four glaucoma specialists. A protocol was implemented for harmonising data including consensus-based interpretation as needed. RESULTS: There were 192 eyes imaged with each format. The mean VCDR for slide, 3DD and 2DD was 0.59±0.20, 0.60±0.18 and 0.62±0.17, respectively. The agreement of VCDR for 3DD versus film was κ=0.781 and for 2DD versus film was κ=0.69. Sensitivity (95.2%), specificity (95.2%) and area under the curve (AUC; 0.953) of 3DD imaging to detect notching were better (p=0.03) than for 2DD (90.5%; 88.6%; AUC=0.895). Similarly, sensitivity (77.8%), specificity (98.9%) and AUC (0.883) of 3DD to detect disc haemorrhage were better (p=0.049) than for 2DD (44.4%; 99.5%; AUC=0.72). There was no difference between 3DD and 2DD imaging in detecting disc tilt (p=0.7), peripapillary atrophy (p=0.16), grey crescent (p=0.1) or pallor (p=0.43), although 3D detected sloping better (p=0.013). CONCLUSIONS: Both 3DD and 2DD imaging demonstrates excellent reproducibility in comparison to stereo slide film with experts evaluating VCDR, notching and disc haemorrhage. 3DD in this study was slightly more accurate than 2DD for evaluating disc haemorrhage, notching and sloping.

Risk factors for progression of diabetic retinopathy in Alberta First Nations communities.

OBJECTIVE: The Screening for Limb, I-Eye, Cardiovascular, and Kidney Complications (SLICK) Program was implemented in 1999 to improve diabetic care for Alberta First Nations individuals living on reserve. The purpose of this review is to determine the rate and predictors of progression of diabetic retinopathy (DR) over a 10-year period. DESIGN: Cohort study. PARTICIPANTS: Nine hundred and eighty First Nations patients with diabetes that underwent at least 2 teleophthalmology examinations during the study period. METHODS: Patients underwent serial laboratory testing, and stereoscopic, mydriatic, retinal photography. Modified Early Treatment Diabetic Retinopathy Study grading of retinal images was performed via teleophthalmology. Progression was defined as an increase of 2 or more steps on the Diabetes Control and Complications Trial classification. RESULTS: At baseline, most patients had no diabetic retinopathy (n = 777, 79.3%) whereas 203 people (20.7%) had either nonproliferative DR (n = 179, 18.3%) or proliferative DR (n = 24, 2.5%). Two-step progression occurred in 163 patients (16.6%), with only a minority of these individuals progressing to proliferative DR (n = 23). The median time to progression was 7.6 years. Multivariate Cox regression demonstrated that elevated hemoglobin A1C (hazard ratio [HR] = 1.42; p < 0.0001) and systolic blood pressure (HR = 1.24 per 10 mm Hg; p = 0.009) were independent predictors of progression of DR. CONCLUSIONS: This population-based study has shown that the rate and predictors of progression of DR among First Nations individuals parallels non-First Nations populations, with HbA1C and systolic blood pressure being the strongest predictors. These findings suggest that targeted, individualized care to reduce blood pressure and control blood sugars could reduce progression of diabetic retinopathy, and possibly blindness in First Nations individuals living on reserve.

Comparative genome and evolutionary analysis of naturally occurring Beilong virus in brown and black rats.

Recently, we reported the presence of Beilong virus in spleen and kidney samples of brown rats and black rats, suggesting that these rodents could be natural reservoirs of Beilong virus. In this study, four genomes of Beilong virus from brown rats and black rats were sequenced. Similar to the Beilong virus genome sequenced from kidney mesangial cell line culture, those of J-virus from house mouse and Tailam virus from Sikkim rats, these four genomes from naturally occurring Beilong virus also contain the eight genes (3'-N-P/V/C-M-F-SH-TM-G-L-5'). In these four genomes, the attachment glycoprotein encoded by the G gene consists of 1046 amino acids; but for the original Beilong virus genome sequenced from kidney mesangial cell line, the G CDS was predicted to be prematurely terminated at position 2205 (TGG→TAG), resulting in a 734-amino-acid truncated G protein. This phenomenon of a lack of nonsense mutation in naturally occurring Beilong viruses was confirmed by sequencing this region of 15 additional rodent samples. Phylogenetic analyses showed that the cell line and naturally occurring Beilong viruses were closely clustered, without separation into subgroups. In addition, these viruses were further clustered with J-virus and Tailam virus, with high bootstrap supports of >90%, forming a distinct group in Paramyxoviridae. Brown rats and black rats are natural reservoirs of Beilong virus. Our results also supports that the recently proposed genus, Jeilongvirus, should encompass Beilong virus, J-virus and Tailam virus as members.

IMPACT OF ETHNIC BACKGROUND ON CLINICAL CHARACTERISTICS AND CARDIOVASCULAR RISK FACTORS AMONG PATIENTS WITH PRIMARY HYPERPARATHYROIDISM.

OBJECTIVE: To compare initial laboratory values and cardiovascular risk factors (CRF) among patients with primary hyperparathyroidism (PHPT) of different ethnic backgrounds. METHODS: In this retrospective study, we reviewed 500 charts of PHPT patients who presented at Robert Wood Johnson University Hospital from January 2000 to December 2013. Among these patients were 46 African Americans (AA), 31 Asians (A), 19 Hispanics (H), and 404 Caucasians (C). The following characteristics were compared between the groups: age; body mass index (BMI); levels of serum calcium, intact parathyroid hormone (iPTH), 25-OH vitamin D, and 24-hour urine calcium; and parathyroid adenoma weight. Presence of CRF including BMI, diabetes mellitus, hypertension, and hyperlipidemia were also recorded for comparison. Associations of adenoma weight and several other parameters were also assessed. RESULTS: Among different ethnic groups, AA patients with PHPT had higher iPTH levels compared to the A and C groups (P<.05), while 25-OHD levels were lower in the AA compared to the A and C groups (P<.05). Adenoma weight was significantly greater in AA than in C and A PHPT patients (P<.01). Adenoma weight was positively correlated with iPTH levels (r = 0.493, P <.001) and serum calcium levels (r = 0.255, P<.01). The group BMIs were C: 29.5 ± 6.9, AA: 33.8 ± 10, A: 24.7 ± 3.3, and H: 30.2 ± 6.6. AA patients had a lower rate of renal stones (9%) compared to other groups (21-29%, P<.05). CONCLUSION: The results of our study indicate that AA patients with PHPT presented with a more severe PHPT profile but had lower 24-hour urine calcium and fewer renal stones. AA patients with PHPT also had higher prevalence of CRF when compared to A and C.

Identification and characterization of a novel paramyxovirus, porcine parainfluenza virus 1, from deceased pigs.

We describe the discovery and characterization of a novel paramyxovirus, porcine parainfluenza virus 1 (PPIV-1), from swine. The virus was detected in 12 (3.1 %) of 386 nasopharyngeal and two (0.7 %) of 303 rectal swab samples from 386 deceased pigs by reverse transcription-PCR, with viral loads of up to 10(6) copies ml(-1). Complete genome sequencing and phylogenetic analysis showed that PPIV-1 represented a novel paramyxovirus within the genus Respirovirus, being most closely related to human parainfluenza virus 1 (HPIV-1) and Sendai virus (SeV). In contrast to HPIV-1, PPIV-1 possessed a mRNA editing function in the phosphoprotein gene. Moreover, PPIV-1 was unique among respiroviruses in having two G residues instead of three to five G residues following the A6 run at the editing site. Nevertheless, PPIV-1, HPIV-1 and SeV share common genomic features and may belong to a separate group within the genus Respirovirus. The presence of PPIV-1 in mainly respiratory samples suggests a possible association with respiratory disease, similar to HPIV-1 and SeV.

Risk factors for progression of diabetic retinopathy in Alberta First Nations communities.

OBJECTIVE: The Screening for Limb, I-Eye, Cardiovascular, and Kidney Complications (SLICK) Program was implemented in 1999 to improve diabetic care for Alberta First Nations individuals living on reserve. The purpose of this review is to determine the rate and predictors of progression of diabetic retinopathy (DR) over a 10-year period. DESIGN: Cohort study. PARTICIPANTS: Nine hundred and eighty First Nations patients with diabetes that underwent at least 2 teleophthalmology examinations during the study period. METHODS: Patients underwent serial laboratory testing, and stereoscopic, mydriatic, retinal photography. Modified Early Treatment Diabetic Retinopathy Study grading of retinal images was performed via teleophthalmology. Progression was defined as an increase of 2 or more steps on the Diabetes Control and Complications Trial classification. RESULTS: At baseline, most patients had no diabetic retinopathy (n = 777, 79.3%) whereas 203 people (20.7%) had either nonproliferative DR (n = 179, 18.3%) or proliferative DR (n = 24, 2.5%). Two-step progression occurred in 163 patients (16.6%), with only a minority of these individuals progressing to proliferative DR (n = 23). The median time to progression was 7.6 years. Multivariate Cox regression demonstrated that elevated hemoglobin A1C (hazard ratio [HR] = 1.42; p < 0.0001) and systolic blood pressure (HR = 1.24 per 10 mm Hg; p = 0.009) were independent predictors of progression of DR. CONCLUSIONS: This population-based study has shown that the rate and predictors of progression of DR among First Nations individuals parallels non-First Nations populations, with HbA1C and systolic blood pressure being the strongest predictors. These findings suggest that targeted, individualized care to reduce blood pressure and control blood sugars could reduce progression of diabetic retinopathy, and possibly blindness in First Nations individuals living on reserve.

Recent transmission of a novel alphacoronavirus, bat coronavirus HKU10, from Leschenault's rousettes to pomona leaf-nosed bats: first evidence of interspecies transmission of coronavirus between bats of different suborders.

Although coronaviruses are known to infect various animals by adapting to new hosts, interspecies transmission events are still poorly understood. During a surveillance study from 2005 to 2010, a novel alphacoronavirus, BatCoV HKU10, was detected in two very different bat species, Ro-BatCoV HKU10 in Leschenault's rousettes (Rousettus leschenaulti) (fruit bats in the suborder Megachiroptera) in Guangdong and Hi-BatCoV HKU10 in Pomona leaf-nosed bats (Hipposideros pomona) (insectivorous bats in the suborder Microchiroptera) in Hong Kong. Although infected bats appeared to be healthy, Pomona leaf-nosed bats carrying Hi-BatCoV HKU10 had lower body weights than uninfected bats. To investigate possible interspecies transmission between the two bat species, the complete genomes of two Ro-BatCoV HKU10 and six Hi-BatCoV HKU10 strains were sequenced. Genome and phylogenetic analyses showed that Ro-BatCoV HKU10 and Hi-BatCoV HKU10 represented a novel alphacoronavirus species, sharing highly similar genomes except in the genes encoding spike proteins, which had only 60.5% amino acid identities. Evolution of the spike protein was also rapid in Hi-BatCoV HKU10 strains from 2005 to 2006 but stabilized thereafter. Molecular-clock analysis dated the most recent common ancestor of all BatCoV HKU10 strains to 1959 (highest posterior density regions at 95% [HPDs], 1886 to 2002) and that of Hi-BatCoV HKU10 to 1986 (HPDs, 1956 to 2004). The data suggested recent interspecies transmission from Leschenault's rousettes to Pomona leaf-nosed bats in southern China. Notably, the rapid adaptive genetic change in BatCoV HKU10 spike protein by ~40% amino acid divergence after recent interspecies transmission was even greater than the ~20% amino acid divergence between spike proteins of severe acute respiratory syndrome-related Rhinolophus bat coronavirus (SARSr-CoV) in bats and civets. This study provided the first evidence for interspecies transmission of coronavirus between bats of different suborders.

Feline morbillivirus, a previously undescribed paramyxovirus associated with tubulointerstitial nephritis in domestic cats.

We describe the discovery and isolation of a paramyxovirus, feline morbillivirus (FmoPV), from domestic cat (Felis catus). FmoPV RNA was detected in 56 (12.3%) of 457 stray cats (53 urine, four rectal swabs, and one blood sample) by RT-PCR. Complete genome sequencing of three FmoPV strains showed genome sizes of 16,050 bases, the largest among morbilliviruses, because of unusually long 5' trailer sequences of 400 nt. FmoPV possesses identical gene contents (3'-N-P/V/C-M-F-H-L-5') and is phylogenetically clustered with other morbilliviruses. IgG against FmoPV N protein was positive in 49 sera (76.7%) of 56 RT-PCR-positive cats, but 78 (19.4%) of 401 RT-PCR-negative cats (P < 0.0001) by Western blot. FmoPV was isolated from CRFK feline kidney cells, causing cytopathic effects with cell rounding, detachment, lysis, and syncytia formation. FmoPV could also replicate in subsequent passages in primate Vero E6 cells. Infected cell lines exhibited finely granular and diffuse cytoplasmic fluorescence on immunostaining for FmoPV N protein. Electron microscopy showed enveloped virus with typical "herringbone" appearance of helical N in paramyxoviruses. Histological examination of necropsy tissues in two FmoPV-positive cats revealed interstitial inflammatory infiltrate and tubular degeneration/necrosis in kidneys, with decreased cauxin expression in degenerated tubular epithelial cells, compatible with tubulointerstitial nephritis (TIN). Immunohistochemical staining revealed FmoPV N protein-positive renal tubular cells and mononuclear cells in lymph nodes. A case-control study showed the presence of TIN in seven of 12 cats with FmoPV infection, but only two of 15 cats without FmoPV infection (P < 0.05), suggesting an association between FmoPV and TIN.

Serial transverse enteroplasty for short bowel syndrome: Hong Kong experience.

OBJECTIVE: To report our experience with the first series of serial transverse enteroplasty operations (a novel bowel-lengthening procedure for patients with short bowel syndrome). DESIGN. Case series. SETTING: A tertiary paediatric surgery referral centre in Hong Kong. PATIENTS: Four patients with short bowel syndrome aged 11 months to 14 years underwent serial transverse enteroplasty between November 2007 and June 2010. RESULTS: A total of six such serial procedures were performed; two patients had repeated operations. Median pre-serial transverse enteroplasty small bowel length was 17.5 cm. The median increase in small bowel length was 90%. One patient experienced transient postoperative intestinal obstruction that resolved after conservative management. The median postoperative follow-up period was 31 months. The median enteral nutrition tolerance increased from 24% to 47%. The median weight-for-age z score increased by 0.55, and the median weight-for-height z score increased by 0.98. One patient had successfully weaned off parenteral nutrition. CONCLUSION: Serial transverse enteroplasty is a feasible and safe treatment for short bowel syndrome patients, which helps to improve enteral nutrition and promote growth. Repeated serial transverse enteroplasty can be performed in patients with ultra-short bowel lengths. Follow-up is necessary to assess the long-term outcomes.

Complete genome sequence of a novel paramyxovirus, Tailam virus, discovered in Sikkim rats.

We discovered a novel paramyxovirus, Tailam virus, of subfamily Paramyxovirinae, in the kidneys and spleens of Sikkim rats. The coding potential of its genome (3'-N-P/V/C-M-F-SH-TM-G-L-5') is similar to those of Beilong virus and J virus, with putative proteins having 59.1 to 94.4% and 23.8 to 80.1% amino acid identities to those of Beilong virus and J virus, respectively.

Coexistence of different genotypes in the same bat and serological characterization of Rousettus bat coronavirus HKU9 belonging to a novel Betacoronavirus subgroup.

Rousettus bat coronavirus HKU9 (Ro-BatCoV HKU9), a recently identified coronavirus of novel Betacoronavirus subgroup D, from Leschenault's rousette, was previously found to display marked sequence polymorphism among genomes of four strains. Among 10 bats with complete RNA-dependent RNA polymerase (RdRp), spike (S), and nucleocapsid (N) genes sequenced, three and two sequence clades for all three genes were codetected in two and five bats, respectively, suggesting the coexistence of two or three distinct genotypes of Ro-BatCoV HKU9 in the same bat. Complete genome sequencing of the distinct genotypes from two bats, using degenerate/genome-specific primers with overlapping sequences confirmed by specific PCR, supported the coexistence of at least two distinct genomes in each bat. Recombination analysis using eight Ro-BatCoV HKU9 genomes showed possible recombination events between strains from different bat individuals, which may have allowed for the generation of different genotypes. Western blot assays using recombinant N proteins of Ro-BatCoV HKU9, Betacoronavirus subgroup A (HCoV-HKU1), subgroup B (SARSr-Rh-BatCoV), and subgroup C (Ty-BatCoV HKU4 and Pi-BatCoV HKU5) coronaviruses were subgroup specific, supporting their classification as separate subgroups under Betacoronavirus. Antibodies were detected in 75 (43%) of 175 and 224 (64%) of 350 tested serum samples from Leschenault's rousette bats by Ro-BatCoV HKU9 N-protein-based Western blot and enzyme immunoassays, respectively. This is the first report describing coinfection of different coronavirus genotypes in bats and coronavirus genotypes of diverse nucleotide variation in the same host. Such unique phenomena, and the unusual instability of ORF7a, are likely due to recombination which may have been facilitated by the dense roosting behavior and long foraging range of Leschenault's rousette.