The spiking output of the mouse olfactory bulb encodes large-scale temporal features of natural odor environments.

In natural odor environments, odor travels in plumes. Odor concentration dynamics change in characteristic ways across the width and length of a plume. Thus, spatiotemporal dynamics of plumes have informative features for animals navigating to an odor source. Population activity in the olfactory bulb (OB) has been shown to follow odor concentration across plumes to a moderate degree (Lewis et al., 2021). However, it is unknown whether the ability to follow plume dynamics is driven by individual cells or whether it emerges at the population level. Previous research has explored the responses of individual OB cells to isolated features of plumes, but it is difficult to adequately sample the full feature space of plumes as it is still undetermined which features navigating mice employ during olfactory guided search. Here we released odor from an upwind odor source and simultaneously recorded both odor concentration dynamics and cellular response dynamics in awake, head-fixed mice. We found that longer timescale features of odor concentration dynamics were encoded at both the cellular and population level. At the cellular level, responses were elicited at the beginning of the plume for each trial, signaling plume onset. Plumes with high odor concentration elicited responses at the end of the plume, signaling plume offset. Although cellular level tracking of plume dynamics was observed to be weak, we found that at the population level, OB activity distinguished whiffs and blanks (accurately detected odor presence versus absence) throughout the duration of a plume. Even ~20 OB cells were enough to accurately discern odor presence throughout a plume. Our findings indicate that the full range of odor concentration dynamics and high frequency fluctuations are not encoded by OB spiking activity. Instead, relatively lower-frequency temporal features of plumes, such as plume onset, plume offset, whiffs, and blanks, are represented in the OB.

Embryonically active piriform cortex neurons promote intracortical recurrent connectivity during development.

Neuronal activity plays a critical role in the maturation of circuits that propagate sensory information into the brain. How widely does early activity regulate circuit maturation across the developing brain? Here, we used targeted recombination in active populations (TRAP) to perform a brain-wide survey for prenatally active neurons in mice and identified the piriform cortex as an abundantly TRAPed region. Whole-cell recordings in neonatal slices revealed preferential interconnectivity within embryonically TRAPed piriform neurons and their enhanced synaptic connectivity with other piriform neurons. In vivo Neuropixels recordings in neonates demonstrated that embryonically TRAPed piriform neurons exhibit broad functional connectivity within piriform and lead spontaneous synchronized population activity during a transient neonatal period, when recurrent connectivity is strengthening. Selectively activating or silencing these neurons in neonates enhanced or suppressed recurrent synaptic strength, respectively. Thus, embryonically TRAPed piriform neurons represent an interconnected hub-like population whose activity promotes recurrent connectivity in early development.

Embryonically Active Piriform Cortex Neurons Promote Intracortical Recurrent Connectivity during Development.

Neuronal activity plays a critical role in the maturation of circuits that propagate sensory information into the brain. How widely does early activity regulate circuit maturation across the developing brain? Here, we used Targeted Recombination in Active Populations (TRAP) to perform a brain-wide survey for prenatally active neurons in mice and identified the piriform cortex as an abundantly TRAPed region. Whole-cell recordings in neonatal slices revealed preferential interconnectivity within embryonically TRAPed piriform neurons and their enhanced synaptic connectivity with other piriform neurons. In vivo Neuropixels recordings in neonates demonstrated that embryonically TRAPed piriform neurons exhibit broad functional connectivity within piriform and lead spontaneous synchronized population activity during a transient neonatal period, when recurrent connectivity is strengthening. Selectively activating or silencing of these neurons in neonates enhanced or suppressed recurrent synaptic strength, respectively. Thus, embryonically TRAPed piriform neurons represent an interconnected hub-like population whose activity promotes recurrent connectivity in early development.

The Prehabilitation Radiotherapy Exercise, smoking Habit cessation and Balanced diet Study (PREHABS) protocol to explore the feasibility of embedding behavioural modifications into the clinical pathway for patients undergoing radical radiotherapy for lung cancer.

Patients with curable non-surgical lung cancer are often current smokers, have co-existing medical comorbidities and are treated with curative radiotherapy. To maximise the benefits of modern radiotherapy, there is an urgent need to optimise the patient's health to improve survival and quality of life. METHODS AND ANALYSIS: The Yorkshire Cancer Research-funded Prehabilitation Radiotherapy Exercise, smoking Habit cessation and Balanced diet Study (PREHABS) (L426) is a single-centre prospective feasibility study to assess embedding behavioural changes into the radical radiotherapy pathway of patients with lung cancer. Feasibility will be assessed by measuring acceptability, demand and implementation. The duration of the study is 24 months. PREHABS has two workstreams: the intervention study and the theory of change (ToC) study.Intervention study: PREHABS will commence at the R-IDEAL phase 2 trial (exploratory) based on existing evidence and includes support for smoking cessation, increasing activity and dietary well-being. Patients undergoing radical radiotherapy for lung cancer will be recruited from the oncology department at Leeds Teaching Hospitals NHS Trust (LTHT). ToC study: to maximise the acceptability and adherence to the PREHABS, we will use a ToC approach to qualitatively explore the key barriers and enablers of implementing a tailored programme of 'prehabilitation'. The PREHABS ToC study participants will be recruited from patients with lung cancer undergoing radical radiotherapy and staff from the LTHT oncology department. ANALYSIS: The primary endpoint analysis will report the number of participants and adherence to the study interventions. Secondary endpoints include continued engagement with study interventions post-treatment. The analysis will focus on descriptive statistics. Thematic analysis of the qualitative data from the ToC study will identify consensus on intervention optimisation and delivery. ETHICS AND DISSEMINATION: On 12 May 2021, the Cambridge East Ethics Committee granted ethical approval (21/EE/0048). The study is registered in the National Institute for Health and Care Research (NIHR) portfolio. The results will be disseminated through publication in peer-reviewed scientific journals and presented at conferences. TRIAL REGISTRATION NUMBER: NIHR portfolio 48420.

Optimal management of radiation pneumonitis: Findings of an international Delphi consensus study.

PURPOSE: Radiation pneumonitis (RP) is a dose-limiting toxicity for patients undergoing radiotherapy (RT) for lung cancer, however, the optimal practice for diagnosis, management, and follow-up for RP remains unclear. We thus sought to establish expert consensus recommendations through a Delphi Consensus study. METHODS: In Round 1, open questions were distributed to 31 expert clinicians treating thoracic malignancies. In Round 2, participants rated agreement/disagreement with statements derived from Round 1 answers using a 5-point Likert scale. Consensus was defined as ≥ 75 % agreement. Statements that did not achieve consensus were modified and re-tested in Round 3. RESULTS: Response rate was 74 % in Round 1 (n = 23/31; 17 oncologists, 6 pulmonologists); 82 % in Round 2 (n = 19/23; 15 oncologists, 4 pulmonologists); and 100 % in Round 3 (n = 19/19). Thirty-nine of 65 Round 2 statements achieved consensus; a further 10 of 26 statements achieved consensus in Round 3. In Round 2, there was agreement that risk stratification/mitigation includes patient factors; optimal treatment planning; the basis for diagnosis of RP; and that oncologists and pulmonologists should be involved in treatment. For uncomplicated radiation pneumonitis, an equivalent to 60 mg oral prednisone per day, with consideration of gastroprotection, is a typical initial regimen. However, in this study, no consensus was achieved for dosing recommendation. Initial steroid dose should be administered for a duration of 2 weeks, followed by a gradual, weekly taper (equivalent to 10 mg prednisone decrease per week). For severe pneumonitis, IV methylprednisolone is recommended for 3 days prior to initiating oral corticosteroids. Final consensus statements included that the treatment of RP should be multidisciplinary, the uncertainty of whether pneumonitis is drug versus radiation-induced, and the importance risk stratification, especially in the scenario of interstitial lung disease. CONCLUSIONS: This Delphi study achieved consensus recommendations and provides practical guidance on diagnosis and management of RP.

Stereotactic Body Radiotherapy for Centrally Located Inoperable Early-Stage NSCLC: EORTC 22113-08113 LungTech Phase II Trial Results.

INTRODUCTION: The international phase II single-arm LungTech trial 22113-08113 of the European Organization for Research and Treatment of Cancer assessed the safety and efficacy of stereotactic body radiotherapy (SBRT) in patients with centrally located early-stage NSCLC. METHODS: Patients with inoperable non-metastatic central NSCLC (T1-T3 N0 M0, ≤7cm) were included. After prospective central imaging review and radiation therapy quality assurance for any eligible patient, SBRT (8 × 7.5 Gy) was delivered. The primary endpoint was freedom from local progression probability three years after the start of SBRT. RESULTS: The trial was closed early due to poor accrual related to repeated safety-related pauses in recruitment. Between August 2015 and December 2017, 39 patients from six European countries were included and 31 were treated per protocol and analyzed. Patients were mainly male (58%) with a median age of 75 years. Baseline comorbidities were mainly respiratory (68%) and cardiac (48%). Median tumor size was 2.6 cm (range 1.2-5.5) and most cancers were T1 (51.6%) or T2a (38.7%) N0 M0 and of squamous cell origin (48.4%). Six patients (19.4%) had an ultracentral tumor location. The median follow-up was 3.6 years. The rates of 3-year freedom from local progression and overall survival were 81.5% (90% confidence interval [CI]: 62.7%-91.4%) and 61.1% (90% CI: 44.1%-74.4%), respectively. Cumulative incidence rates of local, regional, and distant progression at three years were 6.7% (90% CI: 1.6%-17.1%), 3.3% (90% CI: 0.4%-12.4%), and 29.8% (90% CI: 16.8%-44.1%), respectively. SBRT-related acute adverse events and late adverse events ≥ G3 were reported in 6.5% (n = 2, including one G5 pneumonitis in a patient with prior interstitial lung disease) and 19.4% (n = 6, including one lethal hemoptysis after a lung biopsy in a patient receiving anticoagulants), respectively. CONCLUSIONS: The LungTech trial suggests that SBRT with 8 × 7.5Gy for central lung tumors in inoperable patients is associated with acceptable local control rates. However, late severe adverse events may occur after completion of treatment. This SBRT regimen is a viable treatment option after a thorough risk-benefit discussion with patients. To minimize potentially fatal toxicity, careful management of dose constraints, and post-SBRT interventions is crucial.

Chemotherapy use and outcomes in patients with stage III or IV small-cell lung cancer in relation to age: An analysis of the English Systemic Anti-Cancer Treatment (SACT) dataset.

Background: We described patterns of chemotherapy use and outcomes in patients with advanced small-cell lung cancer (SCLC) in relation to age using the Systemic Anti-Cancer Treatment dataset. Method: In total, 7,966 patients SCLC (67.6% stage IV) diagnosed between 2014-17 in England, treated with chemotherapy were followed up through 2017. Patterns of chemotherapy use, 30- and 90- mortality rates, and 6- and 12-month and median overall survival (OS) from the initiation of chemotherapy were compared between those below and above the age of 75. Results: Older patients were 6-7 times less likely to receive curative treatment than younger patients regardless of stage. They had more frequent adjustments of treatment and dose reduction (stage III). There were no age differences in dose reduction in stage IV, treatment delayed or stopped earlier than planned. 30-day mortality rates were similar across age groups in stage III SCLC (~4%). Older patients had higher 90-days mortality rates and poorer OS than younger peers. In both stages, OS decreased around the age of 70-75 and were worse in patients with performance status scores ≥2. Conclusion: This study offers a snapshot of chemotherapy use and outcomes in advanced SCLC, notably in older patients, in the pre-immunotherapy era.