An historical and critical study of uraemia

Having endeavoured to fulfil the intention expressed in the Introduction to collect, and to give a complete and orderly description of all that is of importance in the work and conclusions of investigators on the subject of "uraemia" from its earliest days up to the present time, and also to discuss the modern theories in the light of recent researches with a view to indicating in which direction future investigation is most likely to prove profitable, I propose, in conclusion, to recapitulate concisely the main opinions expressed in the course of the Thesis.1. The terms "Uraemia" and "Latent Uraemia" should be discarded, and, as at present conceived, there is no necessity for the continued description of "uraemia" as a separate entity. 2. "Anephrexia" is suggested as a name for the syndrome which may occur as the result of suppression of urine unassociated with active disease of the kidneys. The symptoms are due to the retention in the body of the substances normally excreted in the urine - "urinary poisoning." 3. "Dysnephrexia" is suggested as a term to indicate the state of the kidneys in all conditions, whether primarily renal or not, in which their excretory functions are impaired, but in which the disability is only partial. This state and that of "Anephrexia "' should be clearly differentiated, and no attempt should be made to attribute them to a common cause. 4, Many of the described symptoms of "uraemia" may be explained as being due to efforts at vicarious excretion. The "uraemic syndrome" may be restricted to the Cerebral and Respiratory groups of symptoms. 5. General vascular changes and chronic renal disease, probably the result of the simultaneous action of a toxin, occur concurrently, though not to the same degree. Clinical "uraemia" may thus occur in two forms. In the first form, cardio-vascular changes are marked and renal function is but little impaired; the acute cerebral symptoms are due to mechanical causes of vascular origin, the chronic symptoms to changes in the cerebral vessels, and the paroxysmal dyspnoea to changes in the vessels of the respiratory centre in the medulla oblongata. In the second form, impairment of renal function is predominant; the cerebral symptoms are due to unidentified toxins, and the paroxysmal dyspnoea to acidaemia; as vascular change is also present this may be an additional factor. 6. The residual nitrogen of the blood in "uraemia" contains toxic products of abnormal - metabolism capable o`f producing "uraemic" symptoms, although none of the suggested substances can be regarded as the specific toxin of "uraemia." The liver may be concerned in the production of these toxins but their origin cannot be entirely attributed to hepatic insufficiency. 7. It would appear to be quite possible for the manifestations of "uraemia" to be produced, in certain cases, by the known nitrogenous substances which the kidneys have failed to excrete. Further investigations are required as to the effects of substances maintained in the blood for long periods at the concentrations found in "uraemia." 8. There is no reason to suppose that either the loss of an hypothetical internal secretion of the kidney, or the production of nephrolysins, is in any way concerned in the causation of "uraemia." 9. In view of the varied symptomatology of "uraemia," it is highly probable that several causes may act in combination. In one case there may be a toxic factor, which in another may be complicated by the effects of acidaemia or of high blood pressure; the diminished calcium content of the blood may increase the excitability of the nerve cells, or the retaine3 products of metabolism may reduce the impermeability of the cerebral vessels to toxins. All possible variations of co- operating influences may be expected to occur in the varied circumstances which lead to the "uraemic state.

Heterogeneity and the Voluntary Provision of Public Goods

We investigate the effects of heterogeneity, incomplete information and communication on aggregate contributions to a public good using the voluntary contribution mechanism in a nonlinear laboratory environment. One-dimensional heterogeneity (heterogeneity in income or preferences) and two-dimensional heterogeneity (heterogeneity in income and preferences) both increase voluntary contributions. The effect is greatest when information is incomplete in the sense that subjects do not know each other’s payoffs. Incomplete information also reduces contributions in the homogeneous case. Communication reverses the relative importance of oneand two-dimensional heterogeneity in promoting cooperation.

Use of hyaluronidase in the comparison between manual and automated hematology analysis with the ADVIA 120 to improve analysis of feline body cavity effusions

Classification of body cavity effusions is an important step in the investigation and diagnosis of disease in cats. Feline inflammatory effusions are often highly proteinaceous and viscous, which can cause clumping of white cells and subsequently inaccurate nucleated cell counts (NCCs) using automated and manual methods. Microscopic assessment of cellularity can also be difficult given the variable thickness of smears and cell clumping, which skews white cell distribution. The ADVIA 120 uses 2 white cell–counting channels, the basophil/lobularity (WBC/baso) and differential/peroxidase channels, which can provide quite different results in highly viscous feline samples and often disagree with smear assessment of cellularity. We investigated the effects of pre-incubation of feline effusion samples with hyaluronidase and its effects on NCCs and cellularity assessment. NCCs were obtained by automated analysis using the ADVIA 120 and by manual counting methods. Agreement was assessed using a Bland–Altman chart. Pretreatment of samples with hyaluronidase resulted in good agreement between the ADVIA basophil channel and manual counting methods in all samples in the study. However, improvements in NCCs after hyaluronidase treatment were significantly greater in clumped samples, and cell distribution of these samples on direct smears was also improved. Therefore, when nucleated cell clumping is observed on a direct smear, pretreatment of the sample with hyaluronidase prior to analysis on an automated analyzer is advised, with the WBC/baso channel displaying the most accurate NCC

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Brf1 loss and not overexpression disrupts tissues homeostasis in the intestine, liver and pancreas

RNA polymerase III (Pol-III) transcribes tRNAs and other small RNAs essential for protein synthesis and cell growth. Pol-III is deregulated during carcinogenesis; however, its role in vivo has not been studied. To address this issue, we manipulated levels of Brf1, a Pol-III transcription factor that is essential for recruitment of Pol-III holoenzyme at tRNA genes in vivo. Knockout of Brf1 led to embryonic lethality at blastocyst stage. In contrast, heterozygous Brf1 mice were viable, fertile and of a normal size. Conditional deletion of Brf1 in gastrointestinal epithelial tissues, intestine, liver and pancreas, was incompatible with organ homeostasis. Deletion of Brf1 in adult intestine and liver induced apoptosis. However, Brf1 heterozygosity neither had gross effects in these epithelia nor did it modify tumorigenesis in the intestine or pancreas. Overexpression of BRF1 rescued the phenotypes of Brf1 deletion in intestine and liver but was unable to initiate tumorigenesis. Thus, Brf1 and Pol-III activity are absolutely essential for normal homeostasis during development and in adult epithelia. However, Brf1 overexpression or heterozygosity are unable to modify tumorigenesis, suggesting a permissive, but not driving role for Brf1 in the development of epithelial cancers of the pancreas and gut

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

The Voluntary Provision of Public Goods under Varying Income Distributions.

The T. C. Bergstrom, L. E. Blume, and H. R. Varian (1986) model of voluntary contributions to public goods predicts increases in public good provision as the distribution of income becomes more unequal. This model is tested in the laboratory. Group behavior conforms to the model but individual behavior does not. Individuals with low incomes overcontribute to the public good; individuals with high incomes undercontribute. Coauthors are Stuart Mestelman, Rob Moir, and R. Andrew Muller.