Strategic or Confused Firms? Evidence from “Missing” Transactions in Uganda

Are firms sophisticated maximizers, or do they appear to make mistakes? Using transactions data from Ugandan value-added tax returns, we show that sellers and buyers report different amounts 79% of the time, despite invoices being easily cross-checked. Our estimates suggest that most firms are “advantageous misreporters“, but that 25% are “disadvantageous misreporters” who systematically overreport own sales minus purchases such that their tax liability increases. Similarly, many firms—especially disadvantageous misreporters—fail to VAT-report imported inputs they themselves reported at Customs, increasing their liability. On net, unilateral VAT misreporting cost Uganda about US$384 million in foregone 2013-2016 tax revenue

Collagen α5 and α2(IV) chain coexpression: Analysis of skin biopsies of Alport patients

Alport syndrome is a collagen type IV disease caused by mutations in the COL4A5 gene with the X-linked form being most prevalent. The resultant α5(IV) collagen chain is a component of the glomerular and skin basement membranes (SBMs). Immunofluorescent determination of the α5(IV) chain in skin biopsies is the procedure of choice to identify patients. In 30% of patients, however, the mutant protein is still found in the SBM resulting in a normal staining pattern. In order to minimize or eliminate false results, we compared the distribution of the α2(IV) chain (another SBM component) and the α5(IV) chain by standard double label immunofluorescence (IF) and by confocal laser scanning microcopy. The study was performed on 55 skin biopsies of patients suspected of Alports and five normal control specimens. In normal skin, IF showed the classical linear pattern for both collagens along the basement membrane. Additionally, decreased α5(IV) was found in the bottom of the dermal papillary basement membrane. Confocal analysis confirmed the results and show α5(IV) focal interruptions. In suspected patients, both techniques showed the same rate of abnormal α5(IV) expression: segmental in women and absent in men. Our results show a physiological variation of α5(IV) location with focal interruptions and decreased expression in the bottom of the dermal basement membrane. Comparison of α5(IV) with α2(IV) expression is simple and eliminates technical artifacts

Role of HOXA7 to HOXA13 and PBX1 genes in various forms of MRKH syndrome (congenital absence of uterus and vagina)

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome refers to the congenital absence or severe hypoplasia of the female genital tract, often described as uterovaginal aplasia which is the prime feature of the syndrome. It is the second cause of primary amenorrhea after gonadal dysgenesis and occurs in ~1 in 4500 women. Aetiology of this syndrome remains poorly understood. Frequent association of other malformations with the MRKH syndrome, involving kidneys, skeleton and ears, suggests the involvement of major developmental genes such as those of the HOX family. Indeed mammalian HOX genes are well known for their crucial role during embryogenesis, particularly in axial skeleton, hindbrain and limb development. More recently, their involvement in organogenesis has been demonstrated notably during urogenital differentiation. Although null mutations of HOX genes in animal models do not lead to MRKH-like phenotypes, dominant mutations in their coding sequences or aberrant expression due to mutated regulatory regions could well account for it. Sequence analysis of coding regions of HOX candidate genes and of PBX1, a likely HOX cofactor during Müllerian duct differentiation and kidney morphogenesis, did not reveal any mutation in patients showing various forms of MRKH syndrome. This tends to show that HOX genes are not involved in MRKH syndrome. However it does not exclude that other mechanisms leading to HOX dysfunction may account for the syndrome

Alu-Alu Recombination Underlying the First Large Genomic Deletion in GlcNAc-Phosphotransferase Alpha/Beta (GNPTAB) Gene in a MLII Alpha/Beta Patient

Mucolipidosis type II α/β is a severe, autosomal recessive lysosomal storage disorder, caused by a defect in the GNPTAB gene that codes for the α/β subunits of the GlcNAc-phosphotransferase. To date, over 100 different mutations have been identified in MLII α/β patients, but no large deletions have been reported. Here we present the first case of a large homozygous intragenic GNPTAB gene deletion (c.3435-386_3602 + 343del897) encompassing exon 19, identified in a ML II α/β patient. Long-range PCR and sequencing methodologies were used to refine the characterization of this rearrangement, leading to the identification of a 21 bp repetitive motif in introns 18 and 19. Further analysis revealed that both the 5' and 3' breakpoints were located within highly homologous Alu elements (Alu-Sz in intron 18 and Alu-Sq2, in intron 19), suggesting that this deletion has probably resulted from Alu-Alu unequal homologous recombination. RT-PCR methods were used to further evaluate the consequences of the alteration for the processing of the mutant pre mRNA GNPTAB, revealing the production of three abnormal transcripts: one without exon 19 (p.Lys1146_Trp1201del); another with an additional loss of exon 20 (p.Arg1145Serfs*2), and a third in which exon 19 was substituted by a pseudoexon inclusion consisting of a 62 bp fragment from intron 18 (p.Arg1145Serfs*16). Interestingly, this 62 bp fragment corresponds to the Alu-Sz element integrated in intron 18.This represents the first description of a large deletion identified in the GNPTAB gene and contributes to enrich the knowledge on the molecular mechanisms underlying causative mutations in ML II.This work was supported by FCT - project PIC/IC/83252/2007 (http://alfa.fct.mctes.pt/). Coutinho MF and Quental S received grants from the FCT (SFRH/BD/48103/2008; SFRH/BPD/64025/2009)

Patient-reported outcome measures for pain in autosomal dominant polycystic kidney disease: A systematic review.

Pain is a common symptom in people with autosomal dominant polycystic kidney disease (ADPKD), but it is assessed and reported inconsistently in research, and the validity of the measures remain uncertain. The aim of this study was to identify the characteristics, content, and psychometric properties of measures for pain used in ADPKD. We conducted a systematic review including all trials and observational studies that reported pain in people with ADPKD. Items from all measures were categorized into content and measurement dimensions of pain. We assessed the general characteristics and psychometric properties of all measures. 118 studies, we identified 26 measures: 12 (46%) measures were developed for a non-ADPKD population, 1 (4%) for chronic kidney disease, 2 (8%) for polycystic liver disease and 11 (42%) specifically for ADPKD. Ten anatomical sites were included, with the lower back the most common (10 measures [39%]), four measurement dimensions (intensity (23 [88%]), frequency (3 [12%]), temporality (2 [8%]), and sensory (21 [81%]), two pain types, nociceptive including visceral (15 [58%]) and somatic (5 [20%]), and neuropathic (2 [8%]), and twelve impact dimensions, where the most frequent was work (5 [31%]). The validation data for the measures were variable and only the ADPKD Impact Scale reported all psychometric domains. The measures for pain in ADPKD varied in terms of content and length, and most had not been validated in ADPKD. A standardized psychometrically robust measure that captures patient-important dimensions of pain is needed to evaluate and manage this debilitating complication of ADPKD

Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease:a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice

Recently, the European Medicines Agency approved the use of the vasopressin V2 receptor antagonist tolvaptan to slow the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adult patients with chronic kidney disease stages 1-3 at initiation of treatment with evidence of rapidly progressing disease. In this paper, on behalf of the ERA-EDTA Working Groups of Inherited Kidney Disorders and European Renal Best Practice, we aim to provide guidance for making the decision as to which ADPKD patients to treat with tolvaptan. The present position statement includes a series of recommendations resulting in a hierarchical decision algorithm that encompasses a sequence of risk-factor assessments in a descending order of reliability. By examining the best-validated markers first, we aim to identify ADPKD patients who have documented rapid disease progression or are likely to have rapid disease progression. We believe that this procedure offers the best opportunity to select patients who are most likely to benefit from tolvaptan, thus improving the benefit-to-risk ratio and cost-effectiveness of this treatment. It is important to emphasize that the decision to initiate treatment requires the consideration of many factors besides eligibility, such as contraindications, potential adverse events, as well as patient motivation and lifestyle factors, and requires shared decision-making with the patient.</p

The 2019 and 2021 International Workshops on Alport Syndrome

In 1927 Arthur Cecil Alport, a South African physician, described a British family with an inherited form of kidney disease that affected males more severely than females and was sometimes associated with hearing loss. In 1961, the eponymous name Alport syndrome was adopted. In the late twentieth century three genes responsible for the disease were discovered: COL4A3, COL4A4, and COL4A5 encoding for the α3, α4, α5 polypeptide chains of type IV collagen, respectively. These chains assemble to form heterotrimers of type IV collagen in the glomerular basement membrane. Scientists, clinicians, patient representatives and their families, and pharma companies attended the 2019 International Workshop on Alport Syndrome, held in Siena, Italy, from October 22 to 26, and the 2021 online Workshop from November 30 to December 4. The main topics included: disease re-naming, acknowledging the need to identify an appropriate term able to reflect considerable clinical variability; a strategy for increasing the molecular diagnostic rate; genotype-phenotype correlation from monogenic to digenic forms; new therapeutics and new therapeutic approaches; and gene therapy using gene editing. The exceptional collaborative climate that was established in the magical medieval setting of Siena continued in the online workshop of 2021. Conditions were established for collaborations between leading experts in the sector, including patients and drug companies, with the aim of identifying a cure for Alport syndrome

Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study

Light chain cast nephropathy (LCCN) in multiple myeloma often leads to severe and poorly reversible acute kidney injury. Severe renal impairment influences the allocation of chemotherapy and its tolerability; it also affects patient survival. Whether renal biopsy findings add to the clinical assessment in predicting renal and patient outcomes in LCCN is uncertain. We retrospectively reviewed clinical presentation, chemotherapy regimens, hematologic response, and renal and patient outcomes in 178 patients with biopsy-proven LCCN from 10 centers in Europe and North America. A detailed pathology review, including assessment of the extent of cast formation, was performed to study correlations with initial presentation and outcomes. Patients presented with a mean estimated glomerular filtration rate (eGFR) of 13 ± 11 mL/min/1.73 m2, and 82% had stage 3 acute kidney injury. The mean number of casts was 3.2/mm2 in the cortex. Tubulointerstitial lesions were frequent: acute tubular injury (94%), tubulitis (82%), tubular rupture (62%), giant cell reaction (60%), and cortical and medullary inflammation (95% and 75%, respectively). Medullary inflammation, giant cell reaction, and the extent of cast formation correlated with eGFR value at LCCN diagnosis. During a median follow-up of 22 months, mean eGFR increased to 43 ± 30 mL/min/1.73 m2. Age, β2-microglobulin, best hematologic response, number of cortical casts per square millimeter, and degree of interstitial fibrosis/tubular atrophy (IFTA) were independently associated with a higher eGFR during follow-up. This eGFR value correlated with overall survival, independently of the hematologic response. This study shows that extent of cast formation and IFTA in LCCN predicts the quality of renal response, which, in turn, is associated with overall survival.info:eu-repo/semantics/publishedVersio