Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial.

BACKGROUND: Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. METHODS: endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations. DISCUSSION: This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. TRIAL REGISTRATION: ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial.

BACKGROUND: Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings. METHODS: endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations. DISCUSSION: The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.

Telemonitoring in chronic ventilatory failure: a new model of survellaince, a pilot study.

BACKGROUND AND AIM: The efficiency of tele-monitoring or tele-assistance in patients with severe chronic ventilatory failure in home mechanical ventilation (HMV) is still being investigated. Our aim was to test the feasibility of a model which consisted in: 1) once a week nocturnal telemonitoring, supervised by a doctor in charge in a Respiratory Intensive Care Unit, who also provided a telephone-counselling (24/7) on demand; 2) a scheduled visit every two months. METHODS: A 2-year observational study was carried out on 16 patients ventilated for at least 1 year and for > or = 8 hours/day. Once a week patients underwent a nocturnal monitoring during HMV. The compliance was evaluated by regular transmission of data and regular follow-up, the level of satisfaction by a telephone-questionnaire. RESULTS: The adherence to the protocol study was good in 9/16 (56%) and poor in 7/16 (44%) patients. For each patient, the mean number of connections was 46.12 +/- 36.39 (70.7% of that expected), in those with good compliance it increased to 63.8 +/- 32.7 (114% of that expected). The median hours of connection was 343 (138-1019) and 89 (0-521) for patients with good and poor compliance respectively, p = 0.038. The mean scheduled visits for patient with good compliance was 6.9 +/- 4.14 (100% of that expected). Emergency visits were avoided in 62.5% of cases. The satisfaction score was higher in compliant versus non compliant patients (p = 0.019). CONCLUSION: This pilot study showed that the telemonitoring system employed was feasible and effective in more compliant patients who claimed a high rate of satisfaction.

Iron lung versus conventional mechanical ventilation in acute exacerbation of COPD.

The aim of this randomised study was to compare the effects of iron lung ventilation (ILV) with invasive mechanical ventilation (IMV) in patients with acute respiratory failure (ARF) due to exacerbation of chronic obstructive pulmonary disease. Forty-four patients with ARF were assigned either to ILV (22 patients) or IMV (22 patients). Primary end-points were the improvement in gas exchange and complications related to mechanical ventilation. On admission ILV and IMV groups did not differ in age, simplified acute physiology score II, arterial oxygen tension (Pa,O2)/inspiratory oxygen fraction (FI,O2), arterial carbon dioxide tension (Pa,CO2) and pH. Compared with baseline, ILV and IMV induced a similar and significant improvement in Pa,O2/FI,O2, Pa,CO2 and pH after 1 h of treatment and at discontinuation of mechanical ventilation. Major complications tended to be more frequent in patients treated with IMV than in those treated with ILV (27.3% versus 4.5%), whereas mortality rate was similar (27.3% versus 18.2%). The ventilator-free days and the length of hospital stay were significantly lower in the ILV than in the IMV group. This study suggests that iron lung ventilation is as effective as invasive mechanical ventilation in improving gas exchange in chronic obstructive pulmonary disease patients with acute respiratory failure, and is associated with a tendency towards a lower rate of major complications.

Effect of assist negative pressure ventilation by microprocessor based iron lung on breathing effort.

BACKGROUND: The lack of patient triggering capability during negative pressure ventilation (NPV) may contribute to poor patient synchrony and induction of upper airway collapse. This study was undertaken to evaluate the performance of a microprocessor based iron lung capable of thermistor triggering. METHODS: The effects of NPV with thermistor triggering were studied in four normal subjects and six patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD) by measuring: (1) the time delay (TDtr) between the onset of inspiratory airflow and the start of assisted breathing; (2) the pressure-time product of the diaphragm (PTPdi); and (3) non-triggering inspiratory efforts (NonTrEf). In patients the effects of negative extrathoracic end expiratory pressure (NEEP) added to NPV were also evaluated. RESULTS: With increasing trigger sensitivity the mean (SE) TDtr ranged from 0.29 (0.02) s to 0.21 (0.01) s (mean difference 0.08 s, 95% CI 0.05 to 0.12) in normal subjects and from 0.30 (0.02) s to 0.21 (0.01) s (mean difference 0.09 s, 95% CI 0.06 to 0.12) in patients with COPD; NonTrEf ranged from 8.2 (1.8)% to 1.2 (0.1)% of the total breaths in normal subjects and from 11.8 (2.2)% to 2.5 (0.4)% in patients with COPD. Compared with spontaneous breathing, PTPdi decreased significantly with NPV both in normal subjects and in patients with COPD. NEEP added to NPV resulted in a significant decrease in dynamic intrinsic PEEP, diaphragm effort exerted in the pre-trigger phase, and NonTrEf. CONCLUSIONS: Microprocessor based iron lung capable of thermistor triggering was able to perform assist NPV with acceptable TDtr, significant unloading of the diaphragm, and a low rate of NonTrEf. NEEP added to NPV improved the synchrony between the patient and the ventilator.

Physiologic effects of negative pressure ventilation in acute exacerbation of chronic obstructive pulmonary disease.

To assess the physiologic effects of continuous negative extrathoracic pressure (CNEP), negative pressure ventilation (NPV), and negative extrathoracic end-expiratory pressure (NEEP) added to NPV in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD), we measured in seven patients ventilatory pattern, arterial blood gases, respiratory mechanics, and pressure- time product of the diaphragm (PTPdi) under four conditions: (1) spontaneous breathing (SB); (2) CNEP (-5 cm H(2)O); (3) NPV; (4) NPV plus NEEP. CNEP and NPV were provided by a microprocessor-based iron lung capable of thermistor-triggering. Compared with SB, CNEP improved slightly but significantly Pa(CO(2 ))and pH, and decreased PTPdi (388 +/- 59 versus 302 +/- 43 cm H(2)O. s, respectively, p < 0.05) and dynamic intrinsic positive end-expiratory pressure (PEEPi) (4.6 +/- 0.5 versus 2.1 +/- 0.3 cm H(2)O, respectively, p < 0.001). NPV increased minute ventilation (V E), improved arterial blood gases, and decreased PTPdi to 34% of value during SB (p < 0.001). NEEP added to NPV further slightly decreased PTPdi and improved patient-ventilator interaction by reducing dynamic PEEPi and nontriggering inspiratory efforts. We conclude that CNEP and NPV, provided by microprocessor-based iron lung, are able to improve ventilatory pattern and arterial blood gases, and to unload inspiratory muscles in patients with acute exacerbation of COPD.

[The influence of laparoscopic cholecystectomy vs laparotomy on the monocyte antigen expression (HLA-DR)]. / L'influenza della colecistectomia laparoscopica versus laparatomica sull'antigene di espressione dei monociti (HLA-DR).

It is well known that surgery significantly decrenses immune responses. Laparoscopic cholecystectomy (LC) is a so called "mini invasive" surgical presidia, and on the basis of this consideration we have investigated if and how the immune response is modified in patients after laparoscopic cholecystectomy compare to patients undergone open cholecystectomy. Immune-activity (neutrophils, total lymfocytes count, lymphocytes subpopulations, HLA-DR) was evaluated in 53 patients one day before surgery and p.o. after 1. 3 and 6 days; 26 patients underwent "open" cholecystectomy and 27 LC. One day after surgery patients with open cholecystectomy showed significant increase (p < = 0.05) of plasma neutrophils, while these parameters were almost unchanged in patients with L.C. Finally monocyte antigen HLA-DR was also reduced in patients with "open" cholecystectomy: in this group we also recorded 2 cases (7.6%) of respiratory tract infection. In conclusion LC, strongly reduces p.o. pain, hospitalization, promotes earlier recovery and return to normal activity, avoiding p.o. immunosuppression, mostly due to conservation of HLA-DR activity, with better p.o. morbidity compare to open surgery.

Negative pressure ventilation in COPD patients with acute on chronic respiratory failure.

Negative pressure ventilators act by exposing the surface of the chest wall to subatmospheric pressure during inspiration. During negative pressure ventilation (NPV), tidal volume is related to the peak of the inspiratory negative pressure and the pressure waveform generated by the ventilator pump; for the same peak of negative pressure a square wave produces a greater tidal volume than a half sine wave. Several uncontrolled studies suggest that NPV may have a potential therapeutic role in the treatment of acute on chronic respiratory failure in patients with chronic obstructive pulmonary disease (COPD), reducing the need for endotracheal intubation. Recently, NPV has been used with a good outcome as a first-line treatment in COPD patients with severe acute respiratory failure and hypoxic hypercapnic coma. The positive results of these reports need to be confirmed by further controlled studies before recommending the generalized use of NPV in COPD patients with acute respiratory failure as standard care.

Intermittent negative pressure ventilation in the treatment of hypoxic hypercapnic coma in chronic respiratory insufficiency.

BACKGROUND: In recent years non-invasive ventilatory techniques have been used successfully in the treatment of acute on chronic respiratory failure (ACRF), but careful selection of patients is essential and a comatose state may represent an exclusion criterion. The aim of this retrospective and uncontrolled study was to evaluate whether a non-invasive ventilatory technique such as the iron lung could also be used successfully in patients with hypoxic hypercapnic coma, thus widening the range for application of non-invasive ventilatory techniques. METHODS: A series of 150 consecutive patients with ACRF and hypoxic hypercapnic coma admitted to our respiratory intensive care unit were evaluated retrospectively. The most common underlying condition was chronic obstructive pulmonary disease (79%). On admission a severe hypoxaemia (Pao2 5.81 (3.01) kPa) and hypercapnia (Paco2 14.88 (2.78) kPa) associated with a decompensated acidosis (pH 7.13 (0.13)) were present, the Glasgow coma score ranged from 3 to 8, and the mean APACHE II score was 31.6 (5.3). All patients underwent intermittent negative pressure ventilation with the iron lung. The study end point was based on a dichotomous classification of treatment failure (defined as death or need for endotracheal intubation) versus therapeutic success. RESULTS: There were 45 treatment failures (30%) and 36 deaths (24%). Nine patients (6%) required intubation because of lack of airway control. The median total duration of ventilation was 27 hours per patient (range 2-274). The 105 successfully treated cases recovered consciousness after a median of four hours (range 1-90) of continuous ventilatory treatment and were discharged after 12.1 (9.0) days. CONCLUSIONS: These results show that, in patients with acute on chronic respiratory failure and hypoxic hypercapnic coma, the iron lung resulted in a high rate of success. As this study has the typical limitations of all retrospective and uncontrolled studies, the results need to be formally confirmed by controlled prospective studies. Confirmation of these results could widen the range of application of non-invasive ventilatory techniques.

Iron lung treatment of acute on chronic respiratory failure: 16 yrs of experience.

Noninvasive ventilatory supports are gaining a prominent position among ventilatory techniques aimed to improve ventilation in patients with acute-on-chronic respiratory failure (ACRF). It has not yet been established whether these techniques can be considered as a preventive measure to avoid the need for endotracheal intubation, or are really another means to provide full ventilatory support. At our respiratory intensive care unit (RICU), the ventilatory treatment of ACRF has, for many years, been based on a conservative method, which relies on the use of a body ventilator (iron lung) providing intermittent negative pressure ventilation (INPV). From 1975 to 1991, we treated ACRF in 2,116 patients with chronic obstructive pulmonary disease (COPD) and 604 patients with restrictive thoracopulmonary disease (RTD). Two thousand and eleven patients (95%) underwent INPV. The mortality rate during hospitalization was 9.9% for the patients as a whole (10% and 8.9% for COPD and RTD patients, respectively). The mean length of stay in the RICU was 10.5 +/- 9.5 days. Furthermore, we report the results of our previous studies which investigated how the iron lung works, and how it affected the short- and long-term prognosis of COPD patients in ACRF. Finally, in 180 patients, we report the effects of INPV provided by iron lung on the treatment of ACRF with hypoxic hypercapnic coma (HHC). INPV resulted in a significant improvement of arterial blood gas values and pH, associated with a progressive recovery of the level of consciousness. Only 13 patients needed intubation and 41 (23%) died during hospitalization.(ABSTRACT TRUNCATED AT 250 WORDS)

[Thyroid carcinoma as cystic nodule. The diagnostic role of cytology by needle aspiration]. / Il carcinoma tiroideo su nodulo cistico. Ruolo diagnostico della citologia per agoaspirazione.

195 patients affected by a cystic thyroid lesion were studied by a Fine Needle Aspiration biopsy (FNAb). 42 patients were operated on account of clinical data, compressive phenomena or cytologic results suggesting a neoplasia. Out of the operated patients, 3 were affected by a carcinoma in the cystic lesion (one "pure" cystic nodule and two "mixed" ones), while three more patients with multinodular goiters showed a carcinomatous lesion in a nodule different from the cystic one. Macroscopic characteristics of the aspirated fluid (quantity and quality) didn't affect the cytologic diagnosis. Cytology was useful in the preoperative diagnosis of benign thyroid nodules (only two false positives out of 42 patients) and was diagnostic in all the three patients affected by a carcinoma in the cystic nodule.