Mapping the Relationship between Health-related Beliefs, Fear, Avoidance, and Depression: Lessons from the Pandemic and Beyond.

The COVID-19 pandemic brought a mental health crisis, with depression symptoms increasing nearly three-fold compared to pre-pandemic levels. To explain this surge and to outline related novel treatment targets for post-pandemic psychiatric interventions, the current study examined cognitive, emotional, and behavioral predictors of depression (in the context of the recent pandemic). Participants completed measures assessing perceived danger, perceived infectiousness, and fear of the coronavirus (COVID-19). Participants also reported symptoms of depression and behavioral tendencies: pandemic-related compulsive checking, cleaning, and avoidance (of activities, situations, places, and people). A multiple mediation model revealed that the relationship between perceived infectiousness of the virus and depression was atemporally mediated by fear of the virus and pandemic-related avoidance of activities, situations, places, and people. Furthermore, avoidance played a uniquely important role in the mediation model. First, it directly mediated the relationship between perceived infectiousness and depression, even when omitting fear from the model. Second, avoidance was a discriminant predictor of depression, as neither pandemic-related checking and reassurance-seeking nor cleaning behavior mediated the relationship between cognition and depressive symptoms. Clinical implications are discussed, including how addressing the relationship between anxiety about viral infections and depression can prospectively increase treatment success as we move beyond the pandemic.

The production of p-cresol sulfate and indoxyl sulfate in vegetarians versus omnivores.

BACKGROUND AND OBJECTIVES: The uremic solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) are generated by colon bacteria acting on food components that escape absorption in the small bowel. The production of these potentially toxic compounds may thus be influenced by diet. This study examined whether production of PCS and IS is different in vegetarians and omnivores. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The production of PCS and IS was assessed by measuring their urinary excretion rates in participants with normal kidney function. Studies were carried out in 15 vegetarians and 11 individuals consuming an unrestricted diet. Participants recorded food intake over 4 days and collected urine over the final 2 days of each of two study periods, which were 1 month apart. RESULTS: Average PCS excretion was 62% lower (95% confidence interval [95% CI], 15-83) and average IS excretion was 58% lower (95% CI, 39-71) in vegetarians than in participants consuming an unrestricted diet. Food records revealed that lower excretion of PCS and IS in vegetarians was associated with a 69% higher (95% CI, 20-139) fiber intake and a 25% lower (95% CI, 3-42) protein intake. PCS and IS excretion rates varied widely among individual participants and were not closely correlated with each other but tended to remain stable in individual participants over 1 month. CONCLUSIONS: PCS and IS production rates are markedly lower in vegetarians than in individuals consuming an unrestricted diet.

Selectively increasing the clearance of protein-bound uremic solutes.

BACKGROUND: The toxicity of bound solutes could be better evaluated if we could adjust the clearance of such solutes independent of unbound solutes. This study assessed whether bound solute clearances can be increased while maintaining urea clearance constant during the extended hours of nocturnal dialysis. METHODS: Nine patients on thrice-weekly nocturnal dialysis underwent two experimental dialysis treatments 1 week apart. The experimental treatments were designed to provide the same urea clearance while providing widely different bound solute clearance. One treatment employed a large dialyzer and high dialyzate flow rate (Qd) of 800 mL/min while blood flow (Qb) was 270 mL/min. The other treatment employed a smaller dialyzer and Qd of 300 mL/min while Qb was 350 mL/min. RESULTS: Treatment with the large dialyzer and higher Qd greatly increased the clearances of the bound solutes p-cresol sulfate (PCS: 27±9 versus 14±6 mL/min) and indoxyl sulfate (IS: 26±8 versus 14±5 mL/min) without altering the clearance of urea (204±20 versus 193±16 mL/min). Increasing PCS and IS clearances increased the removal of these solutes (PCS: 375±200 versus 207±86 mg/session; IS: 201±137 versus 153±74 mg/session), while urea removal was not different. CONCLUSIONS: The removal of bound solutes can thus be increased by raising the dialyzate flow and dialyzer size above the low levels sufficient to achieve target Kt/V(urea) during extended treatment. Selectively increasing the clearance of bound solutes provides a potential means to test their toxicity.

Colonic contribution to uremic solutes.

Microbes in the colon produce compounds, normally excreted by the kidneys, which are potential uremic toxins. Although p-cresol sulfate and indoxyl sulfate are well studied examples, few other compounds are known. Here, we compared plasma from hemodialysis patients with and without colons to identify and further characterize colon-derived uremic solutes. HPLC confirmed the colonic origin of p-cresol sulfate and indoxyl sulfate, but levels of hippurate, methylamine, and dimethylamine were not significantly lower in patients without colons. High-resolution mass spectrometry detected more than 1000 features in predialysis plasma samples. Hierarchical clustering based on these features clearly separated dialysis patients with and without colons. Compared with patients with colons, we identified more than 30 individual features in patients without colons that were either absent or present in lower concentration. Almost all of these features were more prominent in plasma from dialysis patients than normal subjects, suggesting that they represented uremic solutes. We used a panel of indole and phenyl standards to identify five colon-derived uremic solutes: α-phenylacetyl-l-glutamine, 5-hydroxyindole, indoxyl glucuronide, p-cresol sulfate, and indoxyl sulfate. However, compounds with accurate mass values matching most of the colon-derived solutes could not be found in standard metabolomic databases. These results suggest that colonic microbes may produce an important portion of uremic solutes, most of which remain unidentified.

Contribution of residual function to removal of protein-bound solutes in hemodialysis.

BACKGROUND AND OBJECTIVES: This study evaluated the contribution of residual function to the removal of solutes for which protein binding limits clearance by hemdialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Solute concentrations were measured in 25 hemodialysis patients with residual urea clearances ranging from 0.1 to 6.2 ml/min per 1.73 m2. Mathematical modeling assessed the effect of residual function on time-averaged solute concentrations. RESULTS: Dialytic clearances of the protein-bound solutes p-cresol sulfate, indoxyl sulfate, and hippurate were reduced in proportion to the avidity of binding and averaged 8±2, 10±3, and 44±13% of the dialytic urea clearance. For each bound solute, the residual clearance was larger in relation to the residual urea clearance. Residual kidney function therefore removed a larger portion of each of the bound solutes than of urea. Increasing residual function was associated with lower plasma levels of p-cresol sulfate and hippurate but not indoxyl sulfate. Wide variation in solute generation tended to obscure the dependence of plasma solute levels on residual function. Mathematical modeling that corrected for this variation indicated that increasing residual function will reduce the plasma level of each of the bound solutes more than the plasma level of urea. CONCLUSIONS: In comparison to urea, solutes than bind to plasma proteins can be more effectively cleared by residual function than by hemodialysis. Levels of such solutes will be lower in patients with residual function than in patients without residual function even if the dialysis dose is reduced based on measurement of residual urea clearance in accord with current guidelines.

Effect of increasing dialyzer mass transfer area coefficient and dialysate flow on clearance of protein-bound solutes: a pilot crossover trial.

BACKGROUND: Protein-bound solutes are poorly cleared by means of conventional hemodialysis because protein binding limits the "free" solute concentration driving diffusion. This study tested the modeled prediction that clearances of bound solutes could be increased by increasing the dialyzer mass transfer area coefficient (K(o)A) and dialysate flow (Q(d)) to greater than the levels used in conventional practice. STUDY DESIGN: Pilot crossover trial. SETTING & PARTICIPANTS: 6 stable long-term hemodialysis patients. INTERVENTION: Study participants underwent an experimental dialysis treatment in which K(o)A and Q(d) were increased by using 2 dialyzers in series and supplying each dialyzer with a Q(d) of 800 mL/min by using 2 dialysis machines. Experimental clearances were compared with those during a conventional treatment with a single dialyzer and Q(d) of 800 mL/min supplied by 1 machine. OUTCOMES: Measured clearances of uremic solutes. MEASUREMENTS: Clearances were measured for urea nitrogen and the bound solutes p-cresol sulfate, indoxyl sulfate, kynurenic acid, and hippurate. RESULTS: Clearances for the bound solutes during conventional treatment were lower than for urea nitrogen (clearance values: urea nitrogen, 255 +/- 16 mL/min; p-cresol sulfate, 23 +/- 4 mL/min; indoxyl sulfate, 30 +/- 7 mL/min; kynurenic acid, 43 +/- 4 mL/min; and hippurate, 115 +/- 11 mL/min). Experimental treatment increased clearances of all solutes (clearance values: urea nitrogen, 318 +/- 19 mL/min; p-cresol sulfate, 37 +/- 6 mL/min; indoxyl sulfate, 46 +/- 8 mL/min; kynurenic acid, 73 +/- 7 mL/min; and hippurate, 165 +/- 17 mL/min). The magnitude of the increases in clearance was greater for bound solutes than for urea nitrogen (increase in clearance: urea nitrogen, 25% +/- 6%; p-cresol sulfate, 66% +/- 19%; indoxyl sulfate, 57% +/- 27%; kynurenic acid, 69% +/- 5%; and hippurate, 44% +/- 15%). LIMITATIONS: A longer term study would be required to determine whether increased dialytic clearance of bound solutes leads to a decrease in plasma solute levels. CONCLUSIONS: Dialytic clearance of protein-bound solutes can be increased by increasing K(o)A and Q(d) to greater than conventional levels.

Update on lymphatic mapping and sentinel node biopsy in the management of patients with melanocytic tumours.

AIMS: To communicate best practices for sentinel lymph node evaluation and assessment of prognosis for patients with melanoma. METHODS: Description and justification of approaches derive from experience with management of more than 2000 melanoma patients evaluated by lymphatic mapping and sentinel node biopsy (LMSNB). RESULTS: Pathologists, by detecting blue dye or carbon particles or alterations in nodal cell populations should attempt to confirm that a node submitted as sentinel is truly sentinel. Pathologists must adequately sample the node by examining multiple tissue sections and determine the presence or absence of metastatic melanoma using sections stained by H&E and immunocytochemistry. Approximately 20% of patients have melanoma in the sentinel node (SN) and accurate evaluation of SN tumour status is the most precise technique for staging clinically localised cutaneous melanoma. The remaining non-sentinel nodes (NSN) in the basin are tumour-free in 67% of patients with melanoma in the SN. Breslow thickness of the primary, the area of tumour in the SN (relative to total nodal area) and density of dendritic leukocytes in the SN paracortex (factors that are combinable in prognostic algorithms) predict metastases in the NSN and the likelihood of recurrence and melanoma-specific death. CONCLUSIONS: Careful pathological analysis is essential to determine the presence or absence of metastatic melanoma in sentinel nodes, findings that indicate whether completion lymphadenectomy is required. Quantitative analysis of the primary melanoma and the amount of tumour in the sentinel node, with evaluation of the dendritic cells in that node, provide invaluable information that predicts non-sentinel node tumour status with increased accuracy and the likelihood of future recurrence and death from melanoma. While these activities require considerable effort from pathologists, their clinical impact justifies the increased workload.

Optimized assessment of sentinel lymph nodes for metastatic melanoma: implications for regional surgery and overall treatment planning.

Correct identification of the sentinel node (SN) and accurate evaluation of this node's tumor status constitute the most precise technique for staging clinically localized cutaneous melanoma. However, even if tumor is present in the SN (as in approximately 20% of patients), the remaining nodes in the basin are often tumor-free. We have found that the Breslow thickness of the primary, the relative area of tumor in the SN (with respect to the area of the SN), and the density of dendritic leukocytes in the SN paracortex not only can predict the likelihood of nonsentinel node metastases but also are correlated with likelihood of tumor recurrence and melanoma-specific survival. The most robust of these predictors is relative tumor area, and this may be used as the basis of practical predictive algorithms.