Racial Disparities in Liver Transplantation for Hepatocellular Carcinoma: Analysis of the National Inpatient Sample From 2007 to 2014.

BACKGROUND: Hepatocellular carcinoma (HCC) remains a deadly disease, with patients' best hope for a cure being liver transplantation; however, access to health care resources, such as donor organs, between ethnic groups has historically been unbalanced. Ensuring equitable access to donor livers is crucial to minimize disparities in HCC outcomes. As a result, we sought to better elucidate the differences in transplantation rates among various ethnic groups. MATERIALS AND METHODS: The National Inpatient Sample (NIS) was utilized to evaluate for disparities in liver transplantation in patients whose primary or secondary diagnosis was recorded as HCC or hepatoma. The study included admissions between 2007 and 2014 to centers with at least 1 documented liver transplant. RESULTS: A total of 7244 transplants were performed over 70,406 weighted admissions. Black race was associated with lower transplantation rates, with an adjusted odds ratio of 0.46 (95% confidence interval: 0.42-0.51, P <0.01) when accounting for a number of possible confounders including socioeconomic and geographic factors. CONCLUSIONS: Our study observed decreased rates of liver transplant in blacks compared with whites for HCC. Furthermore, improved economic status and private insurance had a significantly higher odds ratio for transplantation. Hospital-level studies are needed to clarify confounding factors not apparent in large administrative datasets and help better investigate factors that lead to less optimal transplant rates among blacks. Interventions may include more optimal screening policies and procedures, improved interdisciplinary management, and earlier referrals.

Immunotherapy in progressive supranuclear palsy.

PURPOSE OF REVIEW: Progressive supranuclear palsy (PSP) is a progressive adult-onset neurodegenerative disease. Abnormally, phosphorylated forms of the microtubule-associated protein tau containing four repeat domains (4R-tau) aggregate in neurons. Additionally, increasing evidence suggests that secretion and uptake of fragments of abnormal 4R-tau may play a role in disease progression. This extracellular tau is a natural target for immunotherapy. RECENT FINDINGS: Three monoclonal antibodies targeting extracellular tau are in clinical stages of development. ABBV-8E12 and BIIB092 were safe in Phase 1, but both Phase two studies recently failed futility analyses. UCB0107 recently reported (in abstract form) Phase 1 safety results, and a Phase 2 study is under consideration. Stem cell therapy and the infusion of plasma are also being explored clinically. SUMMARY: The likely role of extracellular tau in the progression of PSP makes tau a natural target for targeted immunotherapy. Clinical trials are still in early stages, and although tau immunotherapy has largely been shown to be safe, efficacy has yet to be demonstrated.

Malignant pleural mesothelioma immune microenvironment and checkpoint expression: correlation with clinical-pathological features and intratumor heterogeneity over time.

Background: Tumor immune microenvironment (TME) plays a key role in malignant pleural mesothelioma (MPM) pathogenesis and treatment outcome, supporting a role of immune checkpoint inhibitors as anticancer approach. This study retrospectively investigated TME and programmed death ligand 1 (PD-L1) expression in naïve MPM cases and their change under chemotherapy. Patients and methods: Diagnostic biopsies of MPM patients were collected from four Italian and one Slovenian cancer centers. Pathological assessment of necrosis, inflammation, grading, and mitosis was carried out. Ki-67, PD-L1 expression, and tumor infiltrating lymphocytes were detected by immunohistochemistry. When available, the same paired sample after chemotherapy was analyzed. Pathological features and clinical characteristics were correlated to overall survival. Results: TME and PD-L1 expression were assessed in 93 and 65 chemonaive MPM samples, respectively. Twenty-eight samples have not sufficient tumor tissue for PD-L1 expression. Sarcomatoid/biphasic samples were characterized by higher CD8+ T lymphocytes and PD-L1 expression on tumor cells, while epithelioid showed higher peritumoral CD4+ T and CD20+ B lymphocytes. Higher CD8+ T lymphocytes, CD68+ macrophages, and PD-L1 expression were associated with pathological features of aggressiveness (necrosis, grading, Ki-67). MPM cases characterized by higher CD8+ T-infiltrate showed lower response to chemotherapy and worse survival at univariate analysis. Patients stratification according to a combined score including CD8+ T lymphocytes, necrosis, mitosis, and proliferation index showed median overall survival of 11.3 months compared with 16.4 months in cases with high versus low combined score (P < 0.003). Subgroup exploratory analysis of 15 paired samples before and after chemotherapy showed a significant increase in cytotoxic T lymphocytes in MPM samples and PD-L1 expression in immune cells. Conclusions: TME enriched with cytotoxic T lymphocytes is associated with higher levels of macrophages and PD-L1 expression on tumor cells and with aggressive histopathological features, lower response to chemotherapy and shorter survival. The role of chemotherapy as a tumor immunogenicity inducer should be confirmed in a larger validation set.

Resource allocation criteria in a hospital.

INTRODUCTION: Allocate fixed resources among competing users is a challenge in terms of hospital management in order to obtain the best performance considering strategic objectives. In order to address this need, a system of evaluation in an important research and teaching hospital was designed. This study describes resource allocation criteria in a hospital focusing on the evaluation system and its developed application methodology. METHODS: The indicator system allows the strategic management to rapidly detect the priorities in the evaluations of the Strategic, Organizational, Managerial, Economic, Research and Qualitative conditions of each unit. The chosen indicators are expressed with three numerical values, (1 indicating critical status, 2 acceptable conditions and 3 a good operational situation). RESULTS AND DISCUSSION: The adopted evaluation system considered different thematic areas: Strategic, Organizational, Managerial, Economic, Research and Qualitative. In order to define each area, 3 fields of evaluation have been chosen. The indicators have been structured according to a pyramid system allowing creating a single indicator for each area for each unit. Furthermore, a single indicator has been fixed in order to facilitate a first consideration on whether to carry out or not closer examinations of the most critical units. This manuscript describes an attempt to define objective criteria for the allocation of scarce resources in order to achieve the hospital's strategic objectives. The indicators identified allow to obtain an overall score for each unit, which allows the management to prioritize the needs.

Persistent residual errors in motor adaptation tasks: reversion to baseline and exploratory escape.

When movements are perturbed in adaptation tasks, humans and other animals show incomplete compensation, tolerating small but sustained residual errors that persist despite repeated trials. State-space models explain this residual asymptotic error as interplay between learning from error and reversion to baseline, a form of forgetting. Previous work using zero-error-clamp trials has shown that reversion to baseline is not obligatory and can be overcome by manipulating feedback. We posited that novel error-clamp trials, in which feedback is constrained but has nonzero error and variance, might serve as a contextual cue for recruitment of other learning mechanisms that would then close the residual error. When error clamps were nonzero and had zero variance, human subjects changed their learning policy, using exploration in response to the residual error, despite their willingness to sustain such an error during the training block. In contrast, when the distribution of feedback in clamp trials was naturalistic, with persistent mean error but also with variance, a state-space model accounted for behavior in clamps, even in the absence of task success. Therefore, when the distribution of errors matched those during training, state-space models captured behavior during both adaptation and error-clamp trials because error-based learning dominated; when the distribution of feedback was altered, other forms of learning were triggered that did not follow the state-space model dynamics exhibited during training. The residual error during adaptation appears attributable to an error-dependent learning process that has the property of reversion toward baseline and that can suppress other forms of learning.

Vigor of movements and the cost of time in decision making.

If we assume that the purpose of a movement is to acquire a rewarding state, the duration of the movement carries a cost because it delays acquisition of reward. For some people, passage of time carries a greater cost, as evidenced by how long they are willing to wait for a rewarding outcome. These steep discounters are considered impulsive. Is there a relationship between cost of time in decision making and cost of time in control of movements? Our theory predicts that people who are more impulsive should in general move faster than subjects who are less impulsive. To test our idea, we considered elementary voluntary movements: saccades of the eye. We found that in humans, saccadic vigor, assessed using velocity as a function of amplitude, was as much as 50% greater in one subject than another; that is, some people consistently moved their eyes with high vigor. We measured the cost of time in a decision-making task in which the same subjects were given a choice between smaller odds of success immediately and better odds if they waited. We measured how long they were willing to wait to obtain the better odds and how much they increased their wait period after they failed. We found that people that exhibited greater vigor in their movements tended to have a steep temporal discount function, as evidenced by their waiting patterns in the decision-making task. The cost of time may be shared between decision making and motor control.

Decay of motor memories in the absence of error.

When motor commands are accompanied by an unexpected outcome, the resulting error induces changes in subsequent commands. However, when errors are artificially eliminated, changes in motor commands are not sustained but show decay. Why does the adaptation-induced change in motor output decay in the absence of error? A prominent idea is that decay reflects the stability of the memory. We show results that challenge this idea and instead suggest that motor output decays because the brain actively disengages a component of the memory. Humans adapted their reaching movements to a perturbation and were then introduced to a long period of trials in which errors were absent (error-clamp). We found that, in some subjects, motor output did not decay at the onset of the error-clamp block but a few trials later. We manipulated the kinematics of movements in the error-clamp block and found that, as movements became more similar to subjects' natural movements in the perturbation block, the lag to decay onset became longer and eventually reached hundreds of trials. Furthermore, when there was decay in the motor output, the endpoint of decay was not zero but a fraction of the motor memory that was last acquired. Therefore, adaptation to a perturbation installed two distinct kinds of memories: (1) one that was disengaged when the brain detected a change in the task and (2) one that persisted despite it. Motor memories showed little decay in the absence of error if the brain was prevented from detecting a change in task conditions.

[Reorganize hospitals to improve efficiency and quality]. / Riorganizzare gli ospedali per migliorare efficienza e qualità.

The current economic difficulties and the changed epidemiological picture, characterized by an increase in life expectancy, which shows in the elderly, chronically ill and disabled the main, both health and social, care needs,r equires a remark on the hospital network and organization. Today, most of the application assistance is usually at low intensity of care, whereas the acute event is shrinking. The prevalence of hospital admissions concern the elderly, who get into acute events but on a substrate of chronicity and co-morbidity conditions. There must be a new model of hospital network, with the possibility of converting some hospital centres for medium intensity care and selecting few centres for high intensity care, where concentrating the more expensive technology and the skill and expertise of the professional. The -suggestion is a renewed health planning that detects:- hospitals for widespread disease, equipped with emergency war for minor codes-hospital at high intensity of care for emergency-urgency- hospital for particular fields of medical speciality and research.

A multistate epidemic outbreak of Salmonella Goldcoast infection in humans, June 2009 to March 2010: the investigation in Italy.

After an urgent inquiry into a suspected international outbreak of Salmonella Goldcoast infection was launched by Hungary in October 2009 a nationwide multidisciplinary investigation was carried out in Italy. The aims were to verify whether the higher than expected number of cases of S. Goldcoast infection that had occurred in Italy in the previous months were linked to the outbreak in Hungary and to determine their origin. Between June 2009 and March 2010, 79 confirmed cases of S. Goldcoast infection were identified. Of these, 17 were part of three different point-source outbreaks probably associated with the consumption of salami. Eating salami was also reported by 20 of the 39 sporadic cases that could be interviewed. Fifteen strains of S. Goldcoast isolated from the cases were typed by pulsed-field gel electrophoresis. They shared more than 90% homology with the Hungarian epidemic strain and were also highly similar to S. Goldcoast strains that had been isolated in Italy from pigs and pork-containing food items in 2009 and 2010. Although the origin of the outbreak and the common source linking the Hungarian and the Italian cases could not be definitively identified, our results suggest a possible zoonotic connection of the outbreak cases with the pork production chain.

Predictive value of abbreviated olfactory tests in prodromal Parkinson disease.

There is disagreement in the literature whether olfaction may show specific impairments in Parkinson Disease (PD) and if olfactory tests comprised of selected odors could be more specific for diagnosis. We sought to validate previously proposed subsets of the University of Pennsylvania Smell Identification Test (UPSIT) odors for predicting conversion to PD in an independent, prodromal cohort. Conversion to PD was assessed in 229 participants in the Parkinson At Risk Study who completed baseline olfactory testing with the UPSIT and up to 12 years of clinical and imaging evaluations. No commercially available or proposed subset performed better than the full 40-item UPSIT. The proposed "PD-specific" subsets also did not perform better than expected by chance. We did not find evidence for selective olfactory impairment in Parkinson disease. Shorter odor identification tests, including commercially available 10-12 item tests, may have utility for ease of use and cost, but not for superior predictive value.

Surveillance of acute infectious gastroenteritis (1992-2009) and food-borne disease outbreaks (1996-2009) in Italy, with a focus on the Piedmont and Lombardy regions.

We describe trends in the occurrence of acute infectious gastroenteritis (1992 to 2009) and food-borne disease outbreaks (1996 to 2009) in Italy. In 2002, the Piedmont region implemented a surveillance system for early detection and control of food-borne disease outbreaks; in 2004, the Lombardy region implemented a system for surveillance of all notifiable human infectious diseases. Both systems are internet based. We compared the regional figures with the national mean using official notification data provided by the National Infectious Diseases Notification System (SIMI) and the National Institute of Statistics (ISTAT), in order to provide additional information about the epidemiology of these diseases in Italy. When compared with the national mean, data from the two regional systems showed a significant increase in notification rates of non-typhoid salmonellosis and infectious diarrhea other than non-typhoid salmonellosis, but for foodborne disease outbreaks, the increase was not statistically significant. Although the two regional systems have different objectives and structures, they showed improved sensitivity regarding notification of cases of acute infectious gastroenteritis and, to a lesser extent, food-borne disease outbreaks, and thus provide a more complete picture of the epidemiology of these diseases in Italy.

Epidemiological and clinical characteristics and behaviours of individuals with newly diagnosed HIV infection: a multicentre study in north Italy.

INTRODUCTION: We aimed to investigate socio-demographic, clinical and epidemiological characteristics and behaviours of subjects with new HIV diagnosis. METHODS: We carried out a multi-centre cross-sectional study comprising 17 infectious diseases units in the Lombardy Region, North Italy. All subjects with a first positive test for HIV infection examined in 2008-09 were interviewed using a structured questionnaire. RESULTS: 472 patients were enrolled (mean age 39.8 years, standard deviation [SD] 11.5), mostly males (78%), and born in Italy (77%). The most common routes of HIV transmission were heterosexual intercourse (49%) and sex among men who have sex with men (MSM) (40%). Never/sometimes use of a condom with occasional partners was associated with male gender, heterosexual transmission route, and with >10 sexual partners in their lifetime. 47% had previous HIV negative tests. Having had more than 2 previous HIV negative tests was associated with younger age, MSM transmission route, CD4+ lymphocyte count >350/microl and self-perception of risk. DISCUSSION: This study shows that there is a large portion of the adult population, especially heterosexual men aged 45 years and over, who are at high risk of acquiring and transmitting HIV infection and undergoing the HIV diagnostic test late, due to risk behaviours combined with a low perception of being at risk. Compared to people infected by heterosexual contacts, MSM show a greater awareness of being at risk of infection, but this knowledge has a low impact in reducing at-risk behaviours.

Serial olfactory testing for the diagnosis of prodromal Parkinson's disease in the PARS study.

BACKGROUND: The Parkinson Associated Risk Syndrome (PARS) study was designed to evaluate whether screening with olfactory testing and dopamine transporter (DAT) imaging could identify participants at risk for developing Parkinson's disease (PD). OBJECTIVE: Hyposmia on a single test has been associated with increased risk of PD, but, taken alone, lacks specificity. We evaluated whether repeating olfactory testing improves the diagnostic characteristics of this screening approach. METHODS: Participants completed up to 10 years of clinical and imaging evaluations in the PARS cohort. Olfaction was assessed with the University of Pennsylvania Smell Identification Test at baseline and on average 1.4 years later. Multiple logistic regression and Cox proportional hazards regression were used to estimate the hazard of development of clinical PD or abnormal DAT imaging. RESULTS: Of 186 participants who were initially hyposmic, 28% reverted to normosmia on repeat testing (reverters). No initially normosmic subjects and only 2% of reverters developed DAT imaging progression or clinical PD, compared to 29% of subjects with persistent hyposmia who developed abnormal DAT and 20% who developed clinical PD. The relative risk of clinical conversion to PD was 8.3 (95% CI:0.92-75.2, p = 0.06) and of abnormal DAT scan was 12.5 (2.4-156.2, p = 0.005) for persistent hyposmia, compared to reversion. CONCLUSIONS: Persistent hyposmia on serial olfactory testing significantly increases the risk of developing clinical PD and abnormal DAT imaging, compared to hyposmia on a single test. Repeat olfactory testing may be an efficient and cost-effective strategy to improve identification of at-risk patients for early diagnosis and disease modification studies.

Development and Impact of a Progressive Parental Leave Policy in a Neurology Residency.

Appropriate parental leave policies remain an unmet need in graduate medical education. Although legal and institutional guidelines allow for policies that support parental leave, there are many challenges and perceived barriers to consider in developing and implementing a successful policy. In 2018, we revised the parental leave policy for our neurology residency. Here we describe the development of our policy, measure its effects, and offer guidelines for other programs to develop a similar approach. We propose solutions to commonly encountered problems, focusing on training and education, staffing of clinical services, evolving legal requirements, resident well-being and equity, and financial support.

Healthcare-acquired infections in rehabilitation units of the Lombardy Region, Italy.

BACKGROUND: Little data are available on the frequency and risk factors for infection in patients in rehabilitation units. METHODS: This was a 2-year retrospective cohort study conducted in 131 rehabilitation units (RUs) of the Lombardy Region, including those for patients requiring musculoskeletal, cardiac, respiratory, neurological and general geriatric rehabilitation. RUs were stratified into three groups by infection rate calculated from administrative data, and a random sample of RUs in each group was selected for analysis. Discharges from these RUs were randomly selected for chart review, and healthcare-acquired infection was confirmed using CDC/NHSN definitions. A logistic regression analysis explored the association among demographic variables of age, sex, type of rehabilitation unit, Charlson comorbidity score, and location prior to RU admission for selected infections. RESULTS: For the 3,028 discharges from 28 RUs, hospital administrative data had a sensitivity of 0.45 and a positive predictive value of 0.89 to identify infections in the chart review. At least one infection occurred in 14.9% of patient discharges, with 71% of infections being urinary, 8.0% respiratory, and 5% skin and soft tissue. Urinary infection was associated with female sex [odds ratio (OR) 1.48, 95% confidence interval (CI) 1.13-1.93], age 75-85 years (OR 2.21, 95% CI 1.12-4.34), Charlson comorbidity score of ≥3 (OR 1.54, 95% CI 1.10-2.17), and the transfer from acute care (OR 1.45, 95% CI 1.04-2.02). For respiratory infection, male sex (OR 3.06, 95% CI 1.51-6.18), comorbidity score of 1 or 2 (OR 2.16, 95% CI 1.08-4.36), and transfer from a healthcare setting other than an acute care hospital were independent risks (OR 3.14, 95% CI 1.15-8.53). CONCLUSION: Infections are common in residents of these rehabilitation units, and risk factors may differ with type of infection. The proportion of infections which may be prevented and effective prevention strategies need to be determined.

Autologus platelet gel for the management of persistent alveolar fistula after lung resection.

Postoperative alveolar fistula (AF) associated with pleural cavity (PC) is a serious complication and a therapeutic challenge in thoracic surgery. The purpose of this study was to assess the efficacy of the use of the autologous platelet gel for the treatment of AF and PC. We treated a patient with post lung resection persistent alveolar fistula using a autologous platelet gel, a cellular compose produces at the Division of Immunohaematoligy and Trasfusion. The platelet gel-PRP (Platelet-Rich Plasma) is a biological material made of autologous platelets, extracted from a small amount of the patient's blood, centrifuged at 1100 g for 9 min. The PRP obtained was activated by addition of autologous thrombin and calcium chloride to form a matrix of fibrin (PRFM) thick. The patient presented important air leak after middle lobe wedge resection for solitary lung lesion with standard open decortication for important pleural adhesions post pleuritis. On postoperative day XIII the patient developed a thoracic empyema and consequently underwent a antibiotic pleural irrigation through the chest drainage based on the microbiological analysis of the pleural fluid. After a week we obtained the resolution of the empyema but a residual space remained and air leak persisted. We treated the patient with autologous platelet gel. We administer 7.5 mL of the autologous platelet gel across the chest drainage ever 72 hours for 3 times. After the third application we had the closure of the cavity and the cessation of air leak. Autologous platelet gel is easy to use, safe and inexpensive. It can be considered a valid therapeutic option in selected patients with a alveolar fistula and a lung partial re-expansion. The product consist of a significant amount of cellular components with healing anti-inflammatory an proregenerative properities that permit the body to heal tissue wounds faster and more efficiently. A sterile pleural cavity is fundamental conditions for the final success of the procedure.

[Investigation of potential risk factors for Salmonella enterica subsp enterica serotype Napoli: a nested case-control study in Lombardia region]. / Identificazione di potenziali fattori di rischio per i casi di infezione da Salmonella enterica subsp enterica sierotipo Napoli attraverso uno studio caso-controllo nidificato con- dotto in Regione Lombardia.

Enter-net surveillance system has detected the re-emergence of Salmonella enterica subsp enterica serotype Napoli (S. Napoli) since 2002. Preliminary data show that food vehicle could not be the only one implicated in the transmission of this serotype. A nested case-control study has been conducted using data form a prospective cohort: for each salmonellosis notification in Lombardia from May 2004 to December 2005 an ad hoc epidemiological investigation has been performed. Cases have been defined as subjects affected by salmonellosis with a positive faecal sample for Salmonella serotype Napoli and controls as subjects affected by salmonellosis with a positive faecal sample for Salmonella serotype not Napoli. Among 2185 salmonellosis notifications collected by 12 of 15 Local Health Authorities, we identified 67 cases and 867 controls. Infection due to S. Napoli were significantly more common among subjects with exposure to surface water (adjusted Odds Ratio (OR) = 3,82; 95% Confidence Interval (C.I.)=1,03-14,19), to domestic animals (adjusted OR = 3,22; 95% C.I. = 1,28-8,10) and among person who practice activities connected to surface water (adjusted OR 3,88; 95% C.I.=1,15-13,05) compared to subjects not exposed to these factors. Hyperendemia of S. Napoli could be attributable to an animal reservoir not yet identified: surface water contamination may be a direct (waterborne infection) or indirect (foodborne infection) vehicle for transmission of S. Napoli. behaviour. Regarding the relations of the neuroendocrine parameters and driving behaviour, positive correlations were observed between dopamine levels and frequency of driving violations while a negative relationship was found between adrenaline levels and frequency of driving errors. In conclusion the identification of psycho-physiological variables related to driving risky behaviour might be a useful instrument to design traffic safety programs tailored to high risk subjects.

Overcoming Barriers to Parkinson Disease Trial Participation: Increasing Diversity and Novel Designs for Recruitment and Retention.

Parkinson disease (PD) is highly prevalent among neurodegenerative diseases, affecting a diverse patient population. Despite a general willingness of patients to participate in clinical trials, only a subset of patients enroll in them. Understanding the barriers to trial participation will help to alleviate this discrepancy and improve trial participation. Underrepresented minorities, older patients, and patients with more medical comorbidities in particular are underrepresented in research. In clinical trials, this has the effect of delaying trial completion, exacerbating disparities, and limiting our ability to generalize study results. Efforts to improve trial design and recruitment are necessary to ensure study enrollment reflects the diversity of patients with PD. At the trial design level, broadening inclusion criteria, attending to participant burden, and focusing on trial efficiency may help. At the recruitment stage, increasing awareness, with traditional outreach or digital approaches; improving engagement, particularly with community physicians; and developing targeted recruitment efforts can also help improve enrollment of underrepresented patient groups. The use of technology, for virtual visits, technology-based objective measures, and community engagement, can also reduce participant burden and increase recruitment. By designing trials to consider these barriers to trial participation, we can improve not only the access to research for all our patients but also the quality and generalizability of clinical research in PD.

Free diffusion to and from the inner nuclear membrane of newly synthesized plasma membrane glycoproteins.

Sindbis virus-infected baby hamster kidney (BHK) cells were analyzed by thin section fracture-label. Specific immunolabel with antiviral glycoprotein antibodies was used in conjunction with colloidal gold-conjugated protein A. As we previously reported (Torrisi, M. R., and S. Bonatti, 1985, J. Cell Biol., 101:1300-1306), Sindbis transmembrane glycoproteins are present in the inner nuclear membrane as well as in the outer nuclear membrane, endoplasmic reticulum, Golgi stacks and vesicles, and plasma membranes. Viral glycoproteins located on the inner nuclear membrane resemble those present on the outer membrane in terms of amount, distribution, and preferential partition after fracture. We show in this paper that Sindbis glycoproteins after treatment with cycloheximide are removed from the inner nuclear membrane with the same kinetics as their counterparts present on the outer membrane. This finding strongly suggests that newly synthesized transmembrane glycoproteins may freely diffuse to and from the inner nuclear membrane before entering into the intracellular transport pathway to the plasma membrane.