Optimal Targeted Lockdowns in a Multigroup SIR Model

We study targeted lockdowns in a multigroup SIR model where infection, hospitalization, and fatality rates vary between groups—in particular between the “young,” the “middle-aged,” and the “old.” Our model enables a tractable quantitative analysis of optimal policy. For baseline parameter values for the COVID-19 pandemic applied to the US, we find that optimal policies differentially targeting risk/age groups significantly outperform optimal uniform policies and most of the gains can be realized by having stricter protective measures such as lockdowns on the more vulnerable, old group. Intuitively, a strict and long lockdown for the old both reduces infections and enables less strict lockdowns for the lower-risk groups. (JEL H51, I12, I18, J13, J14)

The role of stromal tumor infiltrating lymphocytes (sTILs) as a predictive biomarker for carboplatin-based neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC).

e12085 Background: High numbers of sTILs are predictive of pCR in TNBCs. This study examines the role of sTILs as a predictive biomarker for carboplatin (Cb) based NACT. Methods: sTILs were scored on 88 pre NACT TNBC biopsies as per the International TILs Working Group and were scored as continuous and categorical variables: 0-10%; 11-25%; 26-49%; ≥50%. OR was calculated using non-pCR as baseline parameter. Results: Patients with sTILs > 10% had increased pCR rates compared to those with sTILs ≤10%: pCR breast (B) (61% vs 31% p = 0.004); pCR breast/axilla (BA) (52% vs 29% p = 0.021). In those treated with Cb, there were no differences in pCR B between sTILs > 10% or ≤10% (67% vs 53%; p = 0.355) or pCR BA (60% vs 53%; p = 0.500). In those who did not receive Cb, sTILs > 10% had increased pCR B (57% vs 15%; p = 0.002) and pCR BA (46% vs 12%; p = 0.005) compared to sTILs ≤10%. Similar trends were seen with sTILs > 25% and ≥50%: differences were seen in patients who did not receive Cb, but not in those treated with Cb. In LPBCs, the addition of Cb did not significantly increase pCR rates: 67% vs 83% for Cb and non-Cb regimens (p = 0.583). In non-LPBC, pCR rates were increased with Cb: pCR B 59% vs 31% (p = 0.017), and pCR BA 56% vs 23% (p = 0.005) for Cb and non-Cb regimens. The association between sTILs and pCR was significant in multivariable models adjusting for grade and Cb. In patients who did not receive Cb (n = 54), increasing sTILs were associated with increased pCR B (OR 0.15 p = 0.004; OR 0.27 p = 0.039; OR 0.10 p = 0.05 for > 10%, > 25%, ≥50%) and pCR BA (OR 0.18 p = 0.019; OR 0.08 p = 0.029 for > 10%, ≥50%). In patients treated with Cb (n = 30), increasing sTILs were not associated with pCR B (OR 1.97 p = 0.581; OR 0.27 p = 0.334; OR 0.50 p = 0.719) or pCR BA (OR 2.93 p = 0.372; OR 0.79 p = 0.831; OR 0.40 p = 0.622 for > 10%, > 25%, ≥50%). Conclusions: sTILs are predictive of pCR: as sTILs increase, pCR rates increase. Tumors with high sTILs had high pCR rates to anthracycline-taxane (AT) NACT. The effect of increasing sTILs on pCR was most notable in patients who did not receive Cb based NACT, suggesting that tumors with high sTILs are inherently sensitive to AT based chemotherapy. Intensifying NACT with Cb could be used to increase pCR rates in patients with low sTILs. sTILs should be explored as a biomarker to intensify chemotherapy in those with low sTILs, and to de-escalate chemotherapy in tumors with high sTILs.

Neurology (Multiple Sclerosis)

Objectives: The objectives of this study are to understand the impact of natalizumab on cognition beyond two years of therapy and to investigate whether baseline characteristics are predictive of clinical response. Methods: This is a single-center, 24-month, observational study. Sixty-three patients treated with natalizumab were assessed prior to monthly infusions using a Cogstate battery and the SDMT. A linear mixed model was conducted with duration of natalizumab therapy as a between-subjects factor (<=2 or >2 years), assessment as a within-subjects factor, and MSSS as a covariate. Results: There were no statistically significant differences between the key demographic variables aside for the MSSS (p=.0074). No patient showed evidence of sustained cognitive deterioration over the 24 month period. Irrespective of time on natalizumab, significant improvements were observed at the group level in executive function, verbal memory and working memory, whereas processing speed and attention remained unchanged. Impaired cognition or any other baseline parameter did not influence the trajectory of cognitive change over 24 months. Conclusion: Our results suggest that natalizumab preserves cognitive function, including the ability to learn, for 4 years and beyond of continuous therapy. This occurs irrespective of baseline characteristics.

Oxygen transport across vasa recta in the renal medulla

In this model of oxygen transport in the renal medullary microcirculation, we predicted that the net amount of oxygen reabsorbed from vasa recta into the interstitium is on the order of 10−6 mmol/s, i.e., significantly lower than estimated medullary oxygen requirements based on active sodium reabsorption. Our simulations confirmed a number of experimental findings. Low medullary Po 2results from the countercurrent arrangement of vessels and an elevated vasa recta permeability to oxygen, as well as high metabolic needs. Diffusional shunting of oxygen between descending vasa recta (DVR) and ascending vasa recta also explains why a 20-mmHg decrease in initial Po 2 at the corticomedullary junction only leads to a small drop in papillary tip Po 2 (<2 mmHg with baseline parameter values). Conversely, small changes in the consumption rate of DVR-supplied oxygen, in blood flow rate, in hematocrit, or in capillary permeability to oxygen, beyond certain values sharply reduce interstitial Po 2. Without erythrocytes, papillary tip Po 2 cannot be maintained above 10 mmHg, even when oxygen consumption is zero.