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Aim: Transbronchial cryobiopsies are increasingly used for the diagnosis of interstitial lung disease (ILD), but there is a lack of published information on the features of specific ILD in cryobiopsies. Here we attempt to provide pathological guidelines for separating usual interstitial pneumonia (UIP) of idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis (FHP) and connective tissue disease‐associated ILD (CTD–ILD) in cryobiopsies. Methods: We examined 120 cryobiopsies from patients with multidisciplinary discussion (MDD)‐established CTD–ILD and compared them to a prior series of 121 biopsies from patients with MDD‐established IPF or FHP. Results: A non‐specific interstitial pneumonia (NSIP) pattern alone was seen in 36 of 120 (30%) CTD–ILD, three of 83 (3.6%) FHP and two of 38 (5.2%) IPF cases, statistically favouring a diagnosis of CTD–ILD. The combination of NSIP + OP was present in 29 of 120 (24%) CTD–ILD, two of 83 (2.4%) FHP and none of 38 (0%) IPF cases, favouring a diagnosis of CTD–ILD. A UIP pattern, defined as fibroblast foci plus any of patchy old fibrosis/fibrosis with architectural distortion/honeycombing, was identified in 28 of 120 (23%) CTD–ILD, 45 of 83 (54%) FHP and 27 of 38 (71%) IPF cases and supported a diagnosis of FHP or IPF. The number of lymphoid aggregates/mm2 and fibroblast foci/mm2 was not different in IPF, CTD–ILD or FHP cases with a UIP pattern. Interstitial giant cells supported a diagnosis of FHP or CTD–ILD over IPF, but were infrequent. Conclusions: In the correct clinical/radiological context the pathological findings of NSIP, and particularly NSIP plus OP, favour a diagnosis of CTD–ILD in a cryobiopsy, but CTD–ILD with a UIP pattern, FHP with a UIP pattern and IPF generally cannot be distinguished. [ABSTRACT FROM AUTHOR]

Objectives Interstitial lung disease (ILD) in CTDs has highly variable morphology. We aimed to identify imaging features and their impact on ILD progression, mortality, and immunosuppression response. Methods Patients with CTD-ILD had high-resolution chest CT (HRCT) reviewed by expert radiologists blinded to clinical data for overall imaging pattern [usual interstitial pneumonia (UIP); non-specific interstitial pneumonia (NSIP); organizing pneumonia (OP); fibrotic hypersensitivity pneumonitis (fHP); and other]. Transplant-free survival and change in percent-predicted forced vital capacity (FVC) were compared using Cox and linear mixed-effects models adjusted for age, sex, smoking, and baseline FVC. FVC decline after immunosuppression was compared with pre-treatment. Results Among 645 CTD-ILD patients, the most frequent CTDs were SSc (n  = 215), RA (n  = 127), and inflammatory myopathies (n  = 100). NSIP was the most common pattern (54%), followed by UIP (20%), fHP (9%), and OP (5%). Compared with the case for patients with UIP, FVC decline was slower in patients with NSIP (by 1.1%/year, 95% CI 0.2, 1.9) or OP (by 3.5%/year, 95% CI 2.0, 4.9), and mortality was lower in patients with NSIP [hazard ratio (HR) 0.65, 95% CI 0.45, 0.93] or OP (HR 0.18, 95% CI 0.05, 0.57), but higher in fHP (HR 1.58, 95% CI 1.01, 2.40). The extent of fibrosis also predicted FVC decline and mortality. After immunosuppression, FVC decline was slower compared with pre-treatment in NSIP (by 2.1%/year, 95% CI 1.4, 2.8), with no change for UIP or fHP. Conclusion Multiple radiologic patterns are possible in CTD-ILD, including a fHP pattern. NSIP and OP were associated with better outcomes and response to immunosuppression, while fHP had worse survival compared with UIP. [ABSTRACT FROM AUTHOR]

The diagnosis of fibrotic hypersensitivity pneumonitis (also referred to as chronic hypersensitivity pneumonitis, hereafter called FHP) is frequently a difficult problem, because many of the clinical, radiologic, and pathologic features [...], Context.--There is interest in using transbronchial cryobiopsies (CBs) for the diagnosis of fibrotic (chronic) hypersensitivity pneumonitis (FHP), but with little information in the literature about what features are diagnostic in CBs. Objective.--To determine, using in silico investigation, whether features supporting a diagnosis of FHP in video-assisted thoracoscopic (VATS) biopsies can be identified in CBs. Design.--In silico circular "cryobiopsies," 5.25 mm in diameter (21.6 [mm.sup.2]), were created on the slides of 15 VATS biopsy cases that had been assigned a 60% or greater confident diagnosis of FHP at a specially devised multidisciplinary discussion. Using stratified random sampling, up to 8 "cryobiopsies" per case were analyzed for the presence of giant cells/granulomas or peribronchiolar metaplasia affecting 50% or more of the bronchioles, features that had statistically supported a diagnosis of FHP on the VATS biopsies in the multidisciplinary discussion exercise. Results.--Giant cells/granulomas were detected with very low sensitivities in the "cryobiopsies." Using peribronchiolar metaplasia in 50% or more of bronchioles alone, the sensitivity/specificity for a diagnosis of FHP of 2 "cryobiopsies" compared to the corresponding VATS biopsy was 0.57/0.63; for 4 "cryobiopsies," 0.86/0.75; and for 8 "cryobiopsies," 0.83/0.71. Adding giant cells/ granulomas slightly improved these numbers to 0.63/0.71 for 2 "cryobiopsies"; 1.00/0.86 for 4; and 1.00/0.80 for 8. Conclusions.--In the setting of a multidisciplinary discussion where FHP is part of the differential diagnostic choices, 4 actual CBs with an area of roughly 20 [mm.sup.2] each should have good sensitivity and reasonable specificity for diagnosing FHP using these specific morphologic criteria. doi: 10.5858/arpa.2020-0176-OA

The population history of Aboriginal Australians remains largely uncharacterized. Here we generate high-coverage genomes for 83 Aboriginal Australians (speakers of Pama-Nyungan languages) and 25 Papuans from the New Guinea Highlands. We find that Papuan and Aboriginal Australian ancestors diversified 25-40 thousand years ago (kya), suggesting pre-Holocene population structure in the ancient continent of Sahul (Australia, New Guinea and Tasmania). However, all of the studied Aboriginal Australians descend from a single founding population that differentiated ~10-32 kya. We infer a population expansion in northeast Australia during the Holocene epoch (past 10,000 years) associated with limited gene flow from this region to the rest of Australia, consistent with the spread of the Pama-Nyungan languages. We estimate that Aboriginal Australians and Papuans diverged from Eurasians 51-72 kya, following a single out-of-Africa dispersal, and subsequently admixed with archaic populations. Finally, we report evidence of selection in Aboriginal Australians potentially associated with living in the desert.

To the Editor.--Although many pulmonologists are adopting transbronchial cryobiopsy, there is a remarkable dearth of information on the specific pathologic features used to diagnose various forms of interstitial lung disease [...]

Dingoes are culturally and ecologically important free-living canids whose ancestors arrived in Australia over 3,000 B.P., likely transported by seafaring people. However, the early history of dingoes in Australia--including the number of founding populations and their routes of introduction--remains uncertain. This uncertainty arises partly from the complex and poorly understood relationship between modern dingoes and New Guinea singing dogs, and suspicions that post-Colonial hybridization has introduced recent domestic dog ancestry into the genomes of many wild dingo populations. In this study, we analyzed genome-wide data from nine ancient dingo specimens ranging in age from 400 to 2,746 y old, predating the introduction of domestic dogs to Australia by European colonists. We uncovered evidence that the continent-wide population structure observed in modern dingo populations had already emerged several thousand years ago. We also detected excess allele sharing between New Guinea singing dogs and ancient dingoes from coastal New South Wales (NSW) compared to ancient dingoes from southern Australia, irrespective of any post-Colonial hybrid ancestry in the genomes of modern individuals. Our results are consistent with several demographic scenarios, including a scenario where the ancestry of dingoes from the east coast of Australia results from at least two waves of migration from source populations with varying affinities to New Guinea singing dogs. We also contribute to the growing body of evidence that modern dingoes derive little genomic ancestry from post-Colonial hybridization with other domestic dog lineages, instead descending primarily from ancient canids introduced to Sahul thousands of years ago. [ABSTRACT FROM AUTHOR]

Many pathologists have never heard of chronic hypersensitivity pneumonitis (CHP), but in the past 15 years, CHP has emerged as an important problem in fibrosing interstitial pneumonias, a problem that [...], Context.--Chronic hypersensitivity pneumonitis (CHP) has emerged from obscurity during the past 15 years and is now recognized as a very common form of fibrosing interstitial pneumonia but one that is frequently misdiagnosed both clinically and on surgical lung biopsy as usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/ IPF) or fibrotic nonspecific interstitial pneumonia.Objective.--To review the pathologic features of CHP.Data Sources.--Clinical, pathology, and radiology literature were used.Conclusions.--Upper lobe-predominant fibrosis and/or air-trapping on computed tomography scan are features of CHP but not UIP/IPF; however, radiologic separation is possible in only about 50% of cases. Morphologically, CHP sometimes mimics UIP/IPF, but CHP often shows isolated foci of peribronchiolar (centrilobular) fibrosis, frequently associated with fibroblast foci, and in CHP, fibrosis may bridge from the centrilobular region to another bronchiole, an interlobular septum, or the pleura ('bridging fibrosis'). This set of findings is uncommon in UIP/IPF. In addition, CHP may produce a picture of fibrotic nonspecific interstitial pneumonia. Although giant cells/granulomas are usually present in subacute hypersensitivity pneumonitis, they are much less frequently found in CHP, and their absence does not contradict the diagnosis. This diagnostic separation is clinically important because CHP is treated differently than UIP/IPF is (immunosuppressive agents versus antifibrotic agents); further, there are some data to suggest that removing the patient from antigen exposure improves outcome, and there is evidence that patients with CHP have a much better survival prognosis after lung transplantation than do patients with UIP/IPF. In most cases, accurate diagnosis of CHP requires consultation among clinicians, radiologists, and pathologists.(Arch Pathol Lab Med. 2018;142:109-119; doi: 10.5858/arpa.2017-0173-RA)

Human pancreatic islet transplantation offers diabetic patients tight glucose control but has Iow graft survival rates. The immunosuppressive drugs that are administered to graft recipients lack the antiinflammatory benefits of corticosteroids because of their diabetogenic effects. The serum protease inhibitor [alpha]1-antitrypsin (AAT) possesses antiinflammatory properties and reduces cytokine-mediated islet damage. In the present study, diabetic mice were grafted with allogeneic islets and treated with AAT monotherapy (n = 24). After 14 days of treatment, mice remained normoglycemic and islet allografts were functional for up to 120 treatment-free days. After graft removal and retransplantation, mice accepted same-strain islets but rejected third-strain islets, thus confirming that specific immune tolerance had been induced. Explanted grafts exhibited a population of T regulatory cells in transplant sites. According to RT-PCR, grafts contained high levels of mRNA for foxp3, cytotoxic T lymphocyte antigen-4, TGF-[beta], IL-10, and IL-1 receptor antagonist; expression of proinflammatory mediators was low or absent. After implantation of skin allografts, AAT-treated mice had greater numbers of foxp3-positive cells in draining lymph nodes (DLNs) compared with control treatment mice. Moreover, dendritic cells in DLNs exhibited an immature phenotype with decreased CD86 activation marker. Although the number of CD3 transcripts decreased in the DLNs, AAT did not affect IL-2 activity in vitro. Thus, AAT monotherapy provides allografts with antiinflammatory conditions that favor development of antigen-specific T regulatory cells. Because AAT treatment in humans is safe, its use during human islet transplantation may be considered. dendritic cells | diabetes | interleukin-1 | interleukin-10 | T-regulatory cells

The mechanisms involved in the genesis of chronic obstructive pulmonary disease (COPD) are poorly defined. This area is complicated and difficult to model because COPD consists of four separate anatomic lesions (emphysema, small airway remodeling, pulmonary hypertension, and chronic bronchitis) and a functional lesion, acute exacerbation; moreover, the disease in humans develops over decades. This review discusses the various animal models that have been used to attempt to recreate human COPD and the advantages and disadvantages of each. None of the models reproduces the exact changes seen in humans, but cigarette smoke-induced disease appears to come the closest, and genetically modified animals also, in some instances, shed light on processes that appear to play a role. chronic obstructive pulmonary disease

Cigarette smoke-induced animal models of chronic obstructive pulmonary disease support the protease-antiprotease hypothesis of emphysema, although which cells and proteases are the crucial actors remains controversial. Inhibition of either serine or metalloproteases produces significant protection against emphysema, but inhibition is invariably accompanied by decreases in the inflammatory response to cigarette smoke, suggesting that these inhibitors do more than just prevent matrix degradation. Direct anti-inflammatory interventions are also effective against the development of emphysema, as are antioxidant strategies; the latter again decrease smokeinduced inflammation. There is increasing evidence for autoimmunity, perhaps directed against matrix components, as a driving force in emphysema. There is intriguing but controversial animal model evidence that failure to repair/failure of lung maintenance also plays a role in the pathogenesis of emphysema. Cigarette smoke produces small airway remodeling in laboratory animals, possibly by direct induction of fibrogenic growth factors in the airway wall, and also produces pulmonary hypertension, at least in part through direct upregulation of vasoactive mediators in the intrapulmonary arteries. Smoke exposure causes goblet cell metaplasia and excess mucus production in the small airways and proximal trachea, but these changes are not good models of either chronic bronchitis or acute exacerbations. Emphysema, small airway remodeling, pulmonary hypertension, and mucus production appear to be at least partially independent processes that may require different therapeutic approaches. animals; emphysema; small airway remodeling; pulmonary hypertension; chronic obstructive pulmonary disease